Neck Domain Research Articles

The Role of Pulmonary Collectins, Surfactant Protein A (SP-A) and Surfactant Protein D (SP-D) in Cancer.

Surfactant proteins A and D (SP-A and SP-D) belong to the collectin subfamily of C-type oligomeric lectins. They are pattern-recognition molecules (PRMs), able to recognise pathogen- or danger-associated molecular patterns (PAMPs, DAMPs) in the presence of Ca2+ cations. That property enables opsonisation or agglutination of non-self or altered/abnormal self cells and contributes to their clearance. Like other collectins, SP-A and SP-D are characterised by the presence of four distinct domains: a cysteine-rich domain (at the N-terminus), a collagen-like region, an α-helical neck domain and a globular carbohydrate-recognition domain (CRD) (at the C-terminus). Pulmonary surfactant is a lipoprotein complex, preventing alveolar collapse by reducing surface tension at the air-liquid interface. SP-A and SP-D, produced by type II alveolar epithelial cells and Clara cells, are not only pattern-recognition molecules but also contribute to the surfactant structure and homeostasis. Moreover, they are expressed in a variety of extrapulmonary sites where they are involved in local immunity. The term "cancer" includes a variety of diseases: tumours start from uncontrolled growth of abnormal cells in any tissue which may further spread to other sites of the body. Many cancers are incurable, difficult to diagnose and often fatal. This short review summarises anti- and pro-tumorigenic associations of SP-A and SP-D as well as perspectives of their usefulness in cancer diagnosis and therapy.

Motor properties of Myosin 5c are modulated by tropomyosin isoforms and inhibited by pentabromopseudilin.

Myosin 5c (Myo5c) is a motor protein that is produced in epithelial and glandular tissues, where it plays an important role in secretory processes. Myo5c is composed of two heavy chains, each containing a generic motor domain, an elongated neck domain consisting of a single α-helix with six IQ motifs, each of which binds to a calmodulin (CaM) or a myosin light chain from the EF-hand protein family, a coiled-coil dimer-forming region and a carboxyl-terminal globular tail domain. Although Myo5c is a low duty cycle motor, when two or more Myo5c-heavy meromyosin (HMM) molecules are linked together, they move processively along actin filaments. We describe the purification and functional characterization of human Myo5c-HMM co-produced either with CaM alone or with CaM and the essential and regulatory light chains Myl6 and Myl12b. We describe the extent to which cofilaments of actin and Tpm1.6, Tpm1.8 or Tpm3.1 alter the maximum actin-activated ATPase and motile activity of the recombinant Myo5c constructs. The small allosteric effector pentabromopseudilin (PBP), which is predicted to bind in a groove close to the actin and nucleotide binding site with a calculated ΔG of -18.44kcal/mol, inhibits the motor function of Myo5c with a half-maximal concentration of 280nM. Using immunohistochemical staining, we determined the distribution and exact localization of Myo5c in endothelial and endocrine cells from rat and human tissue. Particular high levels of Myo5c were observed in insulin-producing β-cells located within the pancreatic islets of Langerhans.

The dynamics of actin protrusions can be controlled by tip-localized myosin motors

Class III myosins localize to inner ear hair cell stereocilia and are thought to be crucial for stereocilia length regulation. Mutations within the motor domain of MYO3A that disrupt its intrinsic motor properties have been associated with non-syndromic hearing loss, suggesting that the motor properties of MYO3A are critical for its function within stereocilia. In this study, we investigated the impact of a MYO3A hearing loss mutation, H442N, using both in vitro motor assays and cell biological studies. Our results demonstrate the mutation causes a dramatic increase in intrinsic motor properties, actin-activated ATPase and in vitro actin gliding velocity, as well as an increase in actin protrusion extension velocity. We propose that both “gain of function” and “loss of function” mutations in MYO3A can impair stereocilia length regulation, which is crucial for stereocilia formation during development and normal hearing. Furthermore, we generated chimeric MYO3A constructs that replace the MYO3A motor and neck domain with the motor and neck domain of other myosins. We found that duty ratio, fraction of ATPase cycle myosin is strongly bound to actin, is a critical motor property that dictates the ability to tip localize within filopodia. In addition, in vitro actin gliding velocities correlated extremely well with filopodial extension velocities over a wide range of gliding and extension velocities. Taken together, our data suggests a model in which tip-localized myosin motors exert force that slides the membrane tip-ward, which can combat membrane tension and enhance the actin polymerization rate that ultimately drives protrusion elongation.

Solution NMR assignments and structure for the dimeric kinesin neck domain.

Kinesin is a motor protein, comprised of two heavy and two light chains that transports cargo along the cytoskeletal microtubule filament network. The heavy chain has a neck domain connecting the ATPase motor head responsible for walking along microtubules, with the stalk and subsequent tail domains that bind cargo. The neck domain consists of a coiled coli homodimer with about five heptad repeats, preceded by a linker region that joins to the ATPase head. Here we report 1H, 15N, and 13C NMR assignments and a solution structure for the kinesin neck domain from rat isoform Kif5c. The calculation of the NMR structure of the homodimer was facilitated by unambiguously assigning sidechain NOEs between heptad a and d positions to interchain contacts, since these positions are too far apart to give sidechain contacts in the monomers. The dimeric coiled coil NMR structure is similar to the previously described X-ray structure, whereas the linker region is disordered in solution but contains a short segment with β-strand propensity- the β-linker. Only the coiled coil is protected from solvent exchange, with ∆G values for hydrogen exchange on the order of 4-6kcal/mol. The high stability of the hydrogen-bonded α-helical structure makes it unlikely that unzippering of the coiled coil is involved in kinesin walking. Rather, the linker region serves as a flexible hinge between the kinesin head and neck.

Age and Sex Differences in the Genetics of Cardiomyopathy

Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing. Pediatric cases (n = 471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n = 926) (34.6% vs 25.9% respectively, p = 0.0015), with variant enrichment in constrained coding regions. Pediatric patients had a higher burden of sarcomere and lower burden of channelopathy gene variants compared to adults. Specifically, pediatric patients had more MYH7 and MYL3 variants in hypertrophic cardiomyopathy, and fewer TTN truncating variants in dilated cardiomyopathy. MYH7 variants clustered in the myosin head and neck domains in children. OBSCN was a top mutated gene in adults, enriched for protein-truncating variants. In dilated cardiomyopathy, female patients had a higher burden of z-disc gene variants compared to males. Genetic differences may explain age and sex-related variability in cardiomyopathy penetrance. Genotype-guided predictions of age of onset can inform pre-test genetic counseling.Graphical Pediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants in MYH7, MYL3, TNNT2, VCL. Adults had a higher burden of OBSCN and TTN variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.

Self-Association of ACE-2 with Different RBD Amounts: A Dynamic Simulation Perspective on SARS-CoV-2 Infection.

Transmissibility of SARS-CoV-2 initially relies on its trimeric Spike-RBDs to tether the ACE-2 on host cells, and enhanced self-association of ACE-2 engaged with Spike facilitates the viral infection. Two primary packing modes of Spike-ACE2 heteroproteins exist potentially due to discrepant amounts of RBDs loading on ACE-2, but the resultant self-association difference is inherently unclear. We used extensive coarse-grained dynamic simulations to characterize the self-association efficiency, the conformation relevance, and the molecular mechanism of ACE-2 with different RBD amounts. It was revealed that the ACE-2 hanging two/full RBDs (Mode-A) rapidly dimerized into the heteroprotein complex in a compact "linear" conformation, while the bare ACE-2 showed weakened self-association and a protein complex. The RBD-tethered ectodomains of ACE-2 presented a more upright conformation relative to the membrane, and the intermolecular ectodomains were predominantly packed by the neck domains, which was obligated to the rapid protein self-association in a compact pattern. Noted is the fact that the ACE-2 tethered by a single RBD (Mode-B) retained considerable self-association efficiency and clustering capability, which unravels the interrelation of ACE-2 colocalization and protein cross-linkage. The molecular perspectives in this study expound the self-association potency of ACE-2 with different RBD amounts and the viral activity implications, which can greatly enhance our comprehension of SARS-CoV-2 infection details.

Footwall geomorphology during necking domain evolution: A new model for the Frøya High, mid‐Norwegian rifted margin

AbstractObservations and modelling results from highly extended regions indicate that detachment fault systems recording displacements of 10 km or more become associated with footwall uplift and back‐rotation. This is commonly explained by the rolling hinge model, which predicts detachment fault back‐rotation and severe dip reduction (<20°) controlled by the amount of extension. Although detachment faults within necking domains at rifted margins often record displacements in orders consistent with those for the rolling hinge model, it is rarely invoked to explain the associated footwall configurations. Our study area encircles the necking domain of the mid‐Norwegian rifted margin, where the Middle Jurassic–Early Cretaceous Klakk Fault Complex (KFC) directly separates the Frøya High from the Rås Basin. The Frøya High represents the eroded footwall of the KFC detachment fault system which records displacements of 20–40 km. Seismic mapping and well correlation across the Frøya High reveal how three erosional unconformities correspond to three laterally extensive top basement segments which follow the strike of the sinuous KFC. The segments differ in terms of dip, basement geomorphology and the composition and age of the sediments that rest unconformably on the top of basement. We attribute the associated cross‐cutting basement unconformities across the Frøya High to footwall uplift and back‐rotation during fluctuating relative sea‐level and repeated subaerial exposure during Middle Jurassic–Early Cretaceous times. We herein introduce a revised tectono‐sedimentary model for the evolution of the Frøya High, with significant implications for sediment (re‐)routing across the high during rifting. The model indicates that spatio‐temporal sediment distribution was ultimately controlled by the process of necking and evolution of the KFC. Our findings indicate a rolling hinge‐type evolution for the KFC and further suggest that the associated mechanisms may be more common in the necking domains of rifted margins than previously assumed.

3D Evolution of Detachment Fault Systems in Necking Domains: Insights From the Klakk Fault Complex and the Frøya High, Mid‐Norwegian Rifted Margin

AbstractDetachment fault systems typically record displacements in the order of 10s of kilometers. The principles that control the growth of smaller magnitude normal faults are not fully applicable to the evolution of detachment fault systems. We use interpretation of 2D and 3D seismic reflection data from the mid‐Norwegian rifted margin to investigate how the structural evolution of a detachment fault interacted with the effects of isostatic footwall rollback to produce complex 3D geometries and control the configuration of associated supradetachment basins. We further investigate the effects of lateral interaction and linkage of extensional detachment faults on the necking domain configuration. In our study area, the domain‐bounding Klakk Fault Complex demonstrates how successive incision may induce a complex structural relief in response to faulting and fault plane folding. We interpret the previously proposed metamorphic core complex within its footwall as an extension‐parallel turtleback‐structure. The now eroded turtleback is flanked by a major supradetachment basin, connecting two main basin segments. We attribute footwall‐ and turtleback exhumation to Middle Jurassic‐Early Cretaceous rifting. The study area further demonstrates how detachment fault geometries can change during rifting and lead to the formation of younger, successively incising fault splays. Lateral linkage between the original detachment fault plane and these fault splays enables displacement along a detachment fault system consisting of fault segments generated at different stages in time. Implicitly, detachment faults are complex 3D systems that change configuration during their evolution, perpetually controlling associated basin formation, footwall configuration, subsidence and uplift patterns.

Red Sea rifting in central Egypt: constraints from the offshore Quseir province

The formation of oceanic crust in the southern and central Red Sea is generally accepted to have started at c. 5 Ma. However, the nature of the crust in the northern Red Sea is still debated. This paper describes the rift architecture, dynamics and evolution of the northern Red Sea and identifies domains that relate to first-order geodynamic processes. The proximal margin domain is located onshore and is characterized by latest Oligocene–Miocene half-graben basins. New seismic interpretations show that the offshore region is a necking domain dominated by low-angle, high-offset extensional faults, which led to the exhumation of lower crustal gabbros at Brothers Islands. Two-dimensional forward models suggest that the necking domain passes into a distal margin domain, where the continental crust thins to <10 km at 120 km from the coast. Sensitivity testing of interpretations for the distal domain indicates a probable scenario where exhumed lower continental crust or serpentinized mantle is present. A comprehensive rift model for the northern Red Sea in the Quseir province accounts for magmatic underplating accompanied by half-graben development at c. 25 Ma, followed by Early Miocene crustal thinning accommodated by an east-dipping detachment fault. A Late Miocene phase with a flip of the detachment geometry led to the present day configuration.

Crust necking of the northeastern South China Sea: Insights from deep seismic data

During rifting, continental crust necks, leading to significant thickness reduction in a few tens of kilometres. However, deformations associated with the necking process remain elusive due to few outcrop examples and a lack of seismic data coverage that clearly images crustal architecture at depth. Here we use deep, high-resolution seismic data across a well-developed necking zone in the northeastern South China Sea passive margin to show the structural style associated with the crustal necking. Seismic stratigraphy in the necking domain can be divided into pre-, syn- and post-rift sequences based on the nature of sequence-bounding unconformities and their relation with faults. Seismic expression of continental crust exhibits two types of reflection characteristics – homogeneous upper crust and layered lower crust. The necking domain shows significant thinning that reduced its thickness from ~30 km to less than over 10 km in a distance of about ~50 km and is characterised by seaward removal of layered lower crust, while the homogeneous upper crust thickness remains largely unchanged in thickness. The necking domain is bounded by inner and outer breakaway complexes that define a portion of flexed crust. Crustal flexure is evidenced by progressive tilting of the necking domain that gradually increases the pre-rift sequence dip from 0° to 10°. Within the tilted necking domain, densely-spaced, landward-dipping minor faults and fractures are organised in a domino configuration, implying a top-to-the-continent movement and a simple shear deformation of the whole continental crust. We suggest that the flexed necking domain could be home to fractured reservoir providing that it is effectively sealed by post-rift sequences.

Structure and supramolecular organization of the canine distemper virus attachment glycoprotein

Canine distemper virus (CDV) is an enveloped RNA morbillivirus that triggers respiratory, enteric, and high incidence of severe neurological disorders. CDV induces devastating outbreaks in wild and endangered animals as well as in domestic dogs in countries associated with suboptimal vaccination programs. The receptor-binding tetrameric attachment (H)-protein is part of the morbilliviral cell entry machinery. Here, we present the cryo-electron microscopy (cryo-EM) structure and supramolecular organization of the tetrameric CDV H-protein ectodomain. The structure reveals that the morbilliviral H-protein is composed of three main domains: stalk, neck, and heads. The most unexpected feature was the inherent asymmetric architecture of the CDV H-tetramer being shaped by the neck, which folds into an almost 90° bent conformation with respect to the stalk. Consequently, two non-contacting receptor-binding H-head dimers, which are also tilted toward each other, are located on one side of an intertwined four helical bundle stalk domain. Positioning of the four protomer polypeptide chains within the neck domain is guided by a glycine residue (G158), which forms a hinge point exclusively in two protomer polypeptide chains. Molecular dynamics simulations validated the stability of the asymmetric structure under near physiological conditions and molecular docking showed that two receptor-binding sites are fully accessible. Thus, this spatial organization of the CDV H-tetramer would allow for concomitant protein interactions with the stalk and head domains without steric clashes. In summary, the structure of the CDV H-protein ectodomain provides new insights into the morbilliviral cell entry system and offers a blueprint for next-generation structure-based antiviral drug discovery.

The architecture of kinesin-3 KLP-6 reveals a multilevel-lockdown mechanism for autoinhibition

Autoinhibition of kinesin-3 ensures the proper spatiotemporal control of the motor activity for intracellular transport, but the underlying mechanism remains elusive. Here, we determine the full-length structure of kinesin-3 KLP-6 in a compact self-folded state. Unexpectedly, all the internal coiled-coil segments and domains in KLP-6 cooperate to successively lock down the neck and motor domains. The first coiled-coil segment is melted into several short helices that work with the motor domain to restrain the entire neck domain. The second coiled-coil segment associates with its neighboring FHA and MBS domains and integrates with the tail MATH domain to form a supramodule that synergistically wraps around the motor domain to trap the nucleotide and hinder the microtubule binding. This multilevel-lockdown mechanism for autoinhibition could be applicable to other kinesin-3 motors.

Identification of facial nerve displaced vertically in locally invasive mucoepidermoid carcinoma of parotid gland: A rare case discussion

One of the most technically challenging surgeries in the head and neck domain is superficial parotidectomy with its definitive step being facial nerve identification. There are certain anatomical landmarks to guide the surgeon in the identification process. However displacement or obliteration of local anatomy can complicate the identification of facial nerve and render the surgery cumbersome. Displacement of the intracranial portion of the facial nerve has been adequately described in literature however there is a stark lacunae in literature regarding displacement of facial nerve in parotid surgeries and associated challenges. We present a case of a displaced facial nerve in a locally invasive mucoepidermoid carcinoma of the parotid gland invading the sternocleidomastoid muscle and retromandibular vein in which a superficial parotidectomy was undertaken.

Focal segmental glomerulosclerosis and proteinuria associated with Myo1E mutations: novel variants and histological phenotype analysis.

Pathogenic mutations in the non-muscle single-headed myosin, myosin 1E (Myo1e), are a rare cause of pediatric focal segmental glomerulosclerosis (FSGS). These mutations are biallelic, to date only reported as homozygous variants in consanguineous families. Myo1e regulates the actin cytoskeleton dynamics and cell adhesion, which are especially important for podocyte functions. DNA and RNA sequencing were used to identify novel MYO1E variants associated with FSGS. We studied the effects of these variants on the localization of Myo1e in kidney sections. We then analyzed the clinical and histological observations of all known pathogenic MYO1E variants. We identified a patient compound heterozygote for two novel variants in MYO1E and a patient homozygous for a deletion of exon 19. Computer modeling predicted these variants to be disruptive. In both patients, Myo1e was mislocalized. As a rule, pathogenic MYO1E variants map to the Myo1e motor and neck domain and are most often associated with steroid-resistant nephrotic syndrome in children 1-11years of age, leading to kidney failure in 4-10years in a subset of patients. The ultrastructural features are the podocyte damage and striking diffuse and global Alport-like glomerular basement membrane (GBM) abnormalities. We hypothesize that MYO1E mutations lead to disruption of the function of podocyte contractile actin cables resulting in abnormalities of the podocytes and the GBM and dysfunction of the glomerular filtration barrier. The characteristic clinicopathological data can help to tentatively differentiate this condition from other genetic podocytopathies and Alport syndrome until genetic testing is done. A higher resolution version of the Graphical abstract is available as Supplementary information.

Quality of life and two-year results of a randomized phase III study of dysphagia-optimized intensity modulated radiotherapy (DO-IMRT) versus standard IMRT (S-IMRT) in head and neck cancer.

6065 Background: Most newly diagnosed oro- & hypopharngeal cancers (OPC, HPC) are treated with (chemo)RT with curative intent but at the consequence of adverse effects on quality of life. We investigated if using DO-IMRT to reduce RT dose to the dysphagia/aspiration related structures (DARS) improved swallowing function compared to S-IMRT. Methods: Patients with T1-4, N0-3, M0 OPC/HPC were randomised 1:1 to S-IMRT (65 Gray (Gy)/30 fractions (f) to primary & nodal tumour; 54Gy/30f to remaining pharyngeal subsite & nodal areas at risk of microscopic disease) or DO-IMRT. The volume of the superior & middle pharyngeal constrictor muscle (PCM) (OPC) or inferior PCM (HPC) lying outside the high-dose target volume was set a mandatory mean dose constraint in DO-IMRT. Treatment allocation was by minimisation balanced by centre, use of induction/concomitant chemotherapy, tumour site & AJCC stage. Primary endpoint was mean MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after RT. Secondary endpoints included University of Washington (UW)-Qol, Performance Status Scale Head & Neck (PSS-HN) domain scores (range: 0-100), swallow volume, swallow capacity and local control. Results: 112 patients (56 S-IMRT, 56 DO-IMRT) were randomised from 22 UK & Ireland centres from 06/2016 - 04/2018. 111/112 had RT doses as prescribed (1 patient died before RT). Outcome measures at 12 and 24 months are summarised below. DO-IMRT had higher MDADI scores at 12 (p = 0.04) and 24 (p = 0.07) months. Clinically important improvements in swallowing function were seen in patients receiving DO-IMRT using PSS-HN domains and the UW-QoL tool. Conclusions: DO-IMRT improved patient reported swallowing function compared with S-IMRT. Improvements were seen in overall MDADI as well as functional scores in both PSS-HN and UW-QoL. Clinical trial information: 25458988. [Table: see text]

DIC-based approach to predict post necking behavior for AA6061, AA7075 and their friction stir welded joints

In a tensile test, the precise measurement of the area at the necking section is crucial for predicting the post-necking true stress-strain behavior. In the conventional theoretical method, this area is linked to the engineering strain using the incompressibility criteria, which is not applicable in the post necking domain. The present work proposes a digital image correlation (DIC)-based technique with two cameras for estimating real-time area reduction at a necking section of a rectangular tensile specimen during a uniaxial tensile test. In the current study, the area at a given section is computed by measuring strain synchronously in the width and thickness planes of a tensile specimen and translating the change in lengths in both planes into a global coordinate system. The area computation of the proposed approach is successfully validated by measuring the necking area of a terminated tensile specimen (stopped before fracture) by optical microscope to an error in the range of 0.12–1.10%. Following verification, the post necking behaviors of aluminum alloys such as AA6061-T6 and AA7075-T6 are assessed. The current approach is further implemented to evaluate the area reduction and post necking behavior of similar and dissimilar friction stir welding (FSW) joints of AA6061-T6 and AA7075-T6 that possess process induced microstructural inhomogeneity. The current experimental approach effectively assessed the area reduction of a similar and dissimilar FSW joint influenced by weld inhomogeneity, which is otherwise complicated to contemplate using an analytical approach.

Mantle exhumation at magma-poor rifted margins controlled by frictional shear zones

The transition zone from continental crust to the mature mid-ocean ridge spreading center of the Iberia-Newfoundland magma-poor rifted margins is mostly composed of exhumed mantle characterized by highs and domes with varying elevation, spacing and shape. The mechanism controlling strain localization and fault migration explaining the geometry of these peridotite ridges is poorly understood. Here we show using forward geodynamic models that multiple out-of-sequence detachments with recurring dip reversal form during magma-poor rifting and mantle exhumation as a consequence of the strength competition between weak frictional-plastic shear zones and the thermally weakened necking domain beneath the exhuming footwall explaining geometry of these peridotite ridges. Model behaviour also shows that fault types and detachment styles vary with spreading rate and fault strength and confirm that these results can be compared to other magma poor passive margins such as along Antarctica-Australia and to ultra-slow mid-ocean spreading systems as the South-West Indian Ridge.

Structures from intact myofibrils reveal mechanism of thin filament regulation through nebulin.

In skeletal muscle, nebulin stabilizes and regulates the length of thin filaments, but the underlying mechanism remains nebulous. In this work, we used cryo-electron tomography and subtomogram averaging to reveal structures of native nebulin bound to thin filaments within intact sarcomeres. This in situ reconstruction provided high-resolution details of the interaction between nebulin and actin, demonstrating the stabilizing role of nebulin. Myosin bound to the thin filaments exhibited different conformations of the neck domain, highlighting its inherent structural variability in muscle. Unexpectedly, nebulin did not interact with myosin or tropomyosin, but it did interact with a troponin T linker through two potential binding motifs on nebulin, explaining its regulatory role. Our structures support the role of nebulin as a thin filament "molecular ruler" and provide a molecular basis for studying nemaline myopathies.

A neuropathy-associated kinesin KIF1A mutation hyper-stabilizes the motor-neck interaction during the ATPase cycle.

The mechanochemical coupling of ATPase hydrolysis and conformational dynamics in kinesin motors facilitates intramolecular interaction cycles between the kinesin motor and neck domains, which are essential for microtubule-based motility. Here, we characterized a charge-inverting KIF1A-E239K mutant that we identified in a family with axonal-type Charcot-Marie-Tooth disease and also in 24 cases in human neuropathies including spastic paraplegia and hereditary sensory and autonomic neuropathy. We show that Glu239 in the β7 strand is a key residue of the motor domain that regulates the motor-neck interaction. Expression of the KIF1A-E239K mutation has decreased ability to complement Kif1a+/- neurons, and significantly decreases ATPase activity and microtubule gliding velocity. X-ray crystallography shows that this mutation causes an excess positive charge on β7, which may electrostatically interact with a negative charge on the neck. Quantitative mass spectrometric analysis supports that the mutation hyper-stabilizes the motor-neck interaction at the late ATP hydrolysis stage. Thus, the negative charge of Glu239 dynamically regulates the kinesin motor-neck interaction, promoting release of the neck from the motor domain upon ATP hydrolysis.

Preservation of the Iberian Tethys paleomargin beneath the eastern Betic mountain range

We obtain P-wave receiver functions from teleseismic earthquake recordings at a dense seismic broadband transect, deployed along 170 km across the Betic mountain range in southeastern Spain. Migrated images show the crustal structure of the orogen in detail. In particular, they reveal the situation of the subducted Iberian paleomargin, with full preservation of the proximal domain and the ∼50 km wide necking domain. Crustal thinning across the necking domain affects mainly the lower continental crust. The Variscan crust of the Tethys margin is bending downward beneath the Betics, reaching ∼45 km depth, and terminates abruptly at a major slab tear. The distal domain of the paleomargin cannot be reconstructed, but the migrated section suggests that material has been exhumed through the subduction channel and integrated into the Betic orogen. This supports an origin of the HP-LT Nevado-Filabride units from subducted, hyperextended Variscan crust. According to our profile, the present-day eastern Betics appear to have a much more significant contribution from metamorphic Iberian crust than previously thought.