Protein Aggregation Diseases Research Articles

Control of amyloid assembly by autoregulation

The assembly of proteins into amyloid fibrils can be an element of both protein aggregation diseases and a functional unit in healthy biological pathways. In both cases, it must be kept under tight control to prevent undesired aggregation. In normophysiology, proteins can self-chaperone amyloidogenic segments by restricting their conformational flexibility in an overall stabilizing protein fold. However, some aggregation-prone segments cannot be controlled in this manner and require additional regulatory elements to limit fibrillation. The present review summarizes different molecular mechanisms that proteins use to control their own assembly into fibrils, such as the inclusion of a chaperoning domain or a blocking segment in the proform, the controlled release of an amyloidogenic region from the folded protein, or the adjustment of fibrillation propensity according to pH. Autoregulatory elements can control disease-related as well as functional fibrillar protein assemblies and distinguish a group of self-regulating amyloids across a wide range of biological functions and organisms.

Reply: Hereditary spastic paraplegia caused by a mutation in the VCP gene VCP: A Jack of all trades in neuro- and myodegeneration?

Sir, de Bot et al. report on a novel autosomal-dominant form of hereditary spastic paraplegia due to a valosin-containing protein (VCP) missense mutation. Mutations of the human VCP gene on chromosome 9p13.3 have previously been described to cause IBMPFD (inclusion body myopathy with early onset Paget’s disease of bone and frontotemporal dementia, OMIM #167320) (for current review on IBMPFD see Nalbandian et al. , 2011) and ALS14 (amyotrophic lateral sclerosis with or without frontotemporal dementia, OMIM #613954) (for current review on ALS see de Carvalho and Swash, 2011). In the light of the complexity of VCP’s multiple cellular functions, dissecting the molecular pathogenesis of these three diseases is a true scientific challenge. VCP is a ubiquitously expressed, abundant and evolutionarily highly conserved member of the type II AAA-ATPase family (ATPases associated with a wide variety of cellular activities). The targeted ablation of VCP in mouse as well as of its orthologue in fruit fly, yeast and a protist is a lethal event (Frohlich et al. , 1991; Leon and McKearin, 1999; Lamb et al. , 2001; Muller et al. , 2007). VCP plays essential roles in a wide variety of cellular processes comprising nuclear envelope reconstruction, cell cycle, post-mitotic Golgi reassembly, suppression of apoptosis, DNA damage response and endocytosis. In addition, VCP has been attributed to exert central roles in several protein quality control pathways (for review of the multiple functions of VCP refer to Yamanaka et al. , 2012). The pathological consequences of VCP missense mutations have thus far primarily been studied in the context of IBMPFD. Within the large group of human protein aggregation diseases, IBMPFD has a unique role, because VCP- and ubiquitin-positive pathological protein aggregates are present in both neuronal and striated muscle cells (Schroder et al. , 2005; Hubbers …

Heat Shock and Caloric Restriction Have a Synergistic Effect on the Heat Shock Response in a sir2.1-dependent Manner in Caenorhabditis elegans

The heat shock response (HSR) is responsible for maintaining cellular and organismal health through the regulation of proteostasis. Recent data demonstrating that the mammalian HSR is regulated by SIRT1 suggest that this response may be under metabolic control. To test this hypothesis, we have determined the effect of caloric restriction in Caenorhabditis elegans on activation of the HSR and have found a synergistic effect on the induction of hsp70 gene expression. The homolog of mammalian SIRT1 in C. elegans is Sir2.1. Using a mutated C. elegans strain with a sir2.1 deletion, we show that heat shock and caloric restriction cooperate to promote increased survivability and fitness in a sir2.1-dependent manner. Finally, we show that caloric restriction increases the ability of heat shock to preserve movement in a polyglutamine toxicity neurodegenerative disease model and that this effect is dependent on sir2.1.

A model of nitric oxide induced α-synuclein misfolding in Parkinson's disease

Inducible nitric oxide synthase (iNOS) upregulation and consequent NO formation are well-recognized neuroinflammatory responses associated with Parkinson's disease (PD). These contribute to nitrosative protein modifications affecting neuronal injury and cell death. Indeed, a pathobiologic signature for PD is Lewy body formation containing misfolded and aggregated forms of alpha-synuclein (α-syn). Moreover, nitration of α-syn promotes protein aggregation in disease. To model such pathological events, we constructed controllable iNOS and bicistronic α-syn-IRES-tTA adeno-associated virus (AAV) expression vectors. Transduction of iNOS and α-syn AAV constructs led to nitration of α-syn in neurons and overexpression of iNOS promoted protein aggregation. We posit that this AAV system mimics critical protein misfolding events associated with the pathogenesis of PD.

21 Concomitant activation of G-protein coupled receptors (GPCR) and sigma1 receptor (Sig1R): a novel pharmacological concept in treatment of Alzheimer's disease (AD)

The M1 muscarinic agonists AF102B (Evoxac: prescribed in Sjogren’s syndrome) and AF267B {successful in Phases I and IIa (Sjogren’s syndrome)} are effective cognitive enhancers and disease modifiers with a wide safety margin. Notably, i) AF102B decreased CSF Abeta in Alzheimer’s disease (AD) patients (Nitsch et al, Ann Neurol 2000); ii) AF267B rescued cognitive deficits and decreased Abeta42 and tau pathologies in 3xTg-AD mice (Caccamo et al, Neuron, 2006); and iii) in transgenic mice overexpressing human alpha-synuclein, AF102B and AF267B decreased brain alpha-synuclein aggregates (A. Fisher, E. Mazliah, B. Hutter-Paier, D. Havas, M. Windisch, ADPD 2011). Thus the M1 muscarinic GPCR appears to be a pivotal target for treatment of AD, Parkinson’s disease (PD) and Lewy body dementia (LBD). We have also hypothesized that concomitant activation of such a GPCR and the molecular chaperone Sig1R may have broader therapeutic implications in AD and related diseases. To achieve such combined activity we designed a low MW (357.5) compound, AF710B. This compound shows a novel mechanism of enhancing neuroprotection and cognition via Sig1R activation and M1 muscarinic modulation, but not resembling sigma1, M1 muscarinic (allosteric or orthosteric) and dual sigma1/M1 agonists, respectively. The effects of AF710B at low concentrations in vitro against neurodegeneration, oxidative stress, Abeta, Tau-phosphorylation and GSK-3beta activation translate into down-regulation of the apoptotic protein Bax and mitochondrial dysfunction, up-regulation of antiapoptotic Bcl2 and possible modulations of downstream kinases (e.g. PKC, PKB, GSK-3beta). AF710B has an exceptional pharmacology being an excellent cognitive enhancer in rats (at 1-30 and 10-100 mcg/kg, po in trihexyphenidyland in MK801-induced passive avoidance impairments, respectively). Furthermore, AF710B is devoid of side effects, having an unprecedented safety margin 50000 (po). In summary, while M1 agonists can alter pathologies in AD, PD and LBD, the unique profile of AF710B indicates widespread therapeutic advantage, inter alia, also on mitochondrial dysfunctions in these and other protein-aggregation related diseases. 22 NPT002: A NOVEL APPROACH FOR TARGETING -AMYLOID AND TAU AGGREGATES IN ALZHEIMER’S DISEASE

57 Immunotherapy of protein aggregation diseases

57 Immunotherapy of protein aggregation diseases

The family of mammalian small heat shock proteins (HSPBs): Implications in protein deposit diseases and motor neuropathies

A number of neurological and muscular disorders are characterized by the accumulation of aggregate-prone proteins and are referred to as protein deposit or protein conformation diseases. Besides some sporadic forms, most of them are genetically inherited in an autosomal dominant manner, although recessive forms also exist. Although genetically very heterogeneous, some of these diseases are the result of mutations in some members of the mammalian small heat shock protein family (sHSP/HSPB), which are key players of the protein quality control system and participate, together with other molecular chaperones and co-chaperones, in the maintenance of protein homeostasis. Thus, on one hand upregulation of specific members of the HSPB family can exert protective effects in protein deposit diseases, such as the polyglutamine diseases. On the other hand, mutations in the HSPBs lead to neurological and muscular disorders, which may be due to a loss-of-function in protein quality control and/or to a gain-of-toxic function, resulting from the aggregation-proneness of the mutants. In this review we summarize the current knowledge about some of the best characterized functions of the HSPBs (e.g. role in cytoskeleton stabilization, chaperone function, anti-aggregation and anti-apoptotic activities), also highlighting differences in the properties of the various HSPBs and how these may counteract protein aggregation diseases. We also describe the mutations in the various HSPBs associated with neurological and muscular disorders and we discuss how gain-of-toxic function mechanisms (e.g. due to the mutated HSPB protein instability and aggregation) and/or loss-of-function mechanisms can contribute to HSPB-associated pathologies. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.

The HSPB8‐BAG3 chaperone complex is upregulated in astrocytes in the human brain affected by protein aggregation diseases

HSPB8 is a small heat shock protein that forms a complex with the co-chaperone BAG3. Overexpression of the HSPB8-BAG3 complex in cells stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, whose accumulation is a hallmark of many neurodegenerative disorders. HSPB8-BAG3 could thus play a protective role in protein aggregation diseases and might be specifically upregulated in response to aggregate-prone protein-mediated toxicity. Here we analysed HSPB8-BAG3 expression levels in post-mortem human brain tissue from patients suffering of the following protein conformation disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease and spinocerebellar ataxia type 3 (SCA3). Western blotting and immunohistochemistry techniques were used to analyse HSPB8 and BAG3 expression levels in fibroblasts from SCA3 patients and post-mortem brain tissues, respectively. In all diseases investigated, we observed a strong upregulation of HSPB8 and a moderate upregulation of BAG3 specifically in astrocytes in the cerebral areas affected by neuronal damage and degeneration. Intriguingly, no significant change in the HSPB8-BAG3 expression levels was observed within neurones, irrespective of their localization or of the presence of proteinaceous aggregates. We propose that the upregulation of HSPB8 and BAG3 may enhance the ability of astrocytes to clear aggregated proteins released from neurones and cellular debris, maintain the local tissue homeostasis and/or participate in the cytoskeletal remodelling that astrocytes undergo during astrogliosis.

Aggrephagy: Selective Disposal of Protein Aggregates by Macroautophagy

Protein aggregation is a continuous process in our cells. Some proteins aggregate in a regulated manner required for different vital functional processes in the cells whereas other protein aggregates result from misfolding caused by various stressors. The decision to form an aggregate is largely made by chaperones and chaperone-assisted proteins. Proteins that are damaged beyond repair are degraded either by the proteasome or by the lysosome via autophagy. The aggregates can be degraded by the proteasome and by chaperone-mediated autophagy only after dissolution into soluble single peptide species. Hence, protein aggregates as such are degraded by macroautophagy. The selective degradation of protein aggregates by macroautophagy is called aggrephagy. Here we review the processes of aggregate formation, recognition, transport, and sequestration into autophagosomes by autophagy receptors and the role of aggrephagy in different protein aggregation diseases.

Quantitative connection between polyglutamine aggregation kinetics and neurodegenerative process in patients with Huntington’s disease

BackgroundDespite enormous progress in elucidating the biophysics of aggregation, no cause-and-effect relationship between protein aggregation and neurodegenerative disease has been unequivocally established. Here, we derived several risk-based stochastic kinetic models that assess genotype/phenotype correlations in patients with Huntington’s disease (HD) caused by the expansion of a CAG repeat. Fascinating disease-specific aspects of HD include the polyglutamine (polyQ)-length dependence of both age at symptoms onset and the propensity of the expanded polyQ protein to aggregate. In vitro, aggregation of polyQ peptides follows a simple nucleated growth polymerization pathway. Our models that reflect polyQ aggregation kinetics in a nucleated growth polymerization divided aggregate process into the length-dependent nucleation and the nucleation-dependent elongation. In contrast to the repeat-length dependent variability of age at onset, recent studies have shown that the extent of expansion has only a subtle effect on the rate of disease progression, suggesting possible differences in the mechanisms underlying the neurodegenerative process.ResultsUsing polyQ-length as an index, these procedures enabled us for the first time to establish a quantitative connection between aggregation kinetics and disease process, including onset and the rate of progression. Although the complexity of disease process in HD, the time course of striatal neurodegeneration can be precisely predicted by the mathematical model in which neurodegeneration occurs by different mechanisms for the initiation and progression of disease processes. Nucleation is sufficient to initiate neuronal loss as a series of random events in time. The stochastic appearance of nucleation in a cell population acts as the constant risk of neuronal cell damage over time, while elongation reduces the risk by nucleation in proportion to the increased extent of the aggregates during disease progression.ConclusionsOur findings suggest that nucleation is a critical step in gaining toxic effects to the cell, and provide a new insight into the relationship between polyQ aggregation and neurodegenerative process in HD.

Aging and the aggregating proteome.

For all organisms promoting protein homeostasis is a high priority in order to optimize cellular functions and resources. However, there is accumulating evidence that aging leads to a collapse in protein homeostasis and widespread non-disease protein aggregation. This review examines these findings and discusses the potential causes and consequences of this physiological aggregation with age in particular in relation to disease protein aggregation and toxicity. Importantly, recent evidence points to unexpected differences in protein-quality-control and susceptibility to protein aggregation between neurons and other cell types. In addition, new insight into the cell-non-autonomous coordination of protein homeostasis by neurons will be presented.

Abstract P184: Rescue of Reductive Stress by Nrf2 Deficiency in Protein Aggregation Cardiomyopathy Mice

Background: We recently discovered that the overexpression of human mutant αB-crystallin (hR120GCryAB) in mouse resulted in protein aggregation cardiomyopathy (PAC) and reductive stress (RS) in the heart tissue (Rajasekaran et.al Cell, 2007). Further, we identified that sustained activation of Nrf2 (nuclear erythroid 2 related factor 2)/ARE signaling as a causal mechanism for RS in the MPAC mice. We hypothesize that abolishing Nrf2 could prevent RS in R120GTG mice and thereby rescue them from cardiomyopathy and heart failure. Methods: To elucidate loss-of-function mechanisms for Nrf2 on RS and MPAC, we produced (1) NTG/WT, (2) R120GTG/WT, (3) R120GTG/Nrf2+/- and (4) R120GTG/Nrf2-/- mice by intercrossing R120GTG X Nrf2-KO. Primarily, we determined the rate of survival and performed echocardiography to understand the degree of pathogenesis and cardiac function over time (n=6-10). Next, we analyzed the redox state and protein/mRNA expression for major antioxidants including enzymes that are involved in glutathione metabolism in the heart. Results: Disruption of Nrf2 prolonged the survival of MPAC mice along with no signs of cardiac dysfunction (by ECHO). The R120GTG mice with Nrf2 deficiency (either Nrf2+/- or Nrf2-/-; n=4) had significantly decreased glutathione (but equal to NTG) levels when compared with R120GTG/WT cohorts. Such a decline in GSH resulted in quenching of “reducing power” to prevent “reductive stress” and facilitated redox homeostasis in the myocardium. Interestingly, the intercross mice showed no cardiac hypertrophy even at 12 months while the R120GTG exhibited 90% mortality due to PAC/heart failure. Further, protein and mRNA levels for major antioxidants were found to be normal in the R120GTG/Nrf2+/- while there was significant down regulation of these parameters in the R120GTG/Nrf2-/- mice when compared to NTG/WT suggesting that Nrf2-independent pathways are inadequate to maintain the antioxidant capacity under stressed conditions. Conclusions: These results demonstrate a critical role for Nrf2 underlying antioxidant potential in the myocardium. Abrogating RS via Nrf2 might be highly relevant to cure the protein aggregation diseases that are coupled with elevated intracellular reducing potential.

TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR

TDP-43 is linked to neurodegenerative diseases including frontotemporal dementia and amyotrophic lateral sclerosis. Mostly localized in the nucleus, TDP-43 acts in conjunction with other ribonucleoproteins as a splicing co-factor. Several RNA targets of TDP-43 have been identified so far, but its role(s) in pathogenesis remains unclear. Using Affymetrix exon arrays, we have screened for the first time for splicing events upon TDP-43 knockdown. We found alternative splicing of the ribosomal S6 kinase 1 (S6K1) Aly/REF-like target (SKAR) upon TDP-43 knockdown in non-neuronal and neuronal cell lines. Alternative SKAR splicing depended on the first RNA recognition motif (RRM1) of TDP-43 and on 5′-GA-3’ and 5′-UG-3′ repeats within the SKAR pre-mRNA. SKAR is a component of the exon junction complex, which recruits S6K1, thereby facilitating the pioneer round of translation and promoting cell growth. Indeed, we found that expression of the alternatively spliced SKAR enhanced S6K1-dependent signaling pathways and the translational yield of a splice-dependent reporter. Consistent with this, TDP-43 knockdown also increased translational yield and significantly increased cell size. This indicates a novel mechanism of deregulated translational control upon TDP-43 deficiency, which might contribute to pathogenesis of the protein aggregation diseases frontotemporal dementia and amyotrophic lateral sclerosis.

LEDGF1-326 Decreases P23H and Wild Type Rhodopsin Aggregates and P23H Rhodopsin Mediated Cell Damage in Human Retinal Pigment Epithelial Cells

BackgroundP23H rhodopsin, a mutant rhodopsin, is known to aggregate and cause retinal degeneration. However, its effects on retinal pigment epithelial (RPE) cells are unknown. The purpose of this study was to determine the effect of P23H rhodopsin in RPE cells and further assess whether LEDGF1-326, a protein devoid of heat shock elements of LEDGF, a cell survival factor, reduces P23H rhodopsin aggregates and any associated cellular damage.MethodsARPE-19 cells were transiently transfected/cotransfected with pLEDGF1-326 and/or pWT-Rho (wild type)/pP23H-Rho. Rhodopsin mediated cellular damage and rescue by LEDGF1-326 was assessed using cell viability, cell proliferation, and confocal microscopy assays. Rhodopsin monomers, oligomers, and their reduction in the presence of LEDGF1-326 were quantified by western blot analysis. P23H rhodopsin mRNA levels in the presence and absence of LEDGF1-326 was determined by real time quantitative PCR.Principal FindingsP23H rhodopsin reduced RPE cell viability and cell proliferation in a dose dependent manner, and disrupted the nuclear material. LEDGF1-326 did not alter P23H rhodopsin mRNA levels, reduced its oligomers, and significantly increased RPE cell viability as well as proliferation, while reducing nuclear damage. WT rhodopsin formed oligomers, although to a smaller extent than P23H rhodopsin. Further, LEDGF1-326 decreased WT rhodopsin aggregates.ConclusionsP23H rhodopsin as well as WT rhodopsin form aggregates in RPE cells and LEDGF1-326 decreases these aggregates. Further, LEDGF1-326 reduces the RPE cell damage caused by P23H rhodopsin. LEDGF1-326 might be useful in treating cellular damage associated with protein aggregation diseases such as retinitis pigmentosa.

Molecular chaperones in protein folding and proteostasis

Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.

Analysis of the Globular Nature of Proteins

Abstract Numerous restraints and simplifications have been de-veloped for methods that anticipate protein structure to reduce the colossal magnitude of possible conforma-tional states. In this study, we investigated if globularity is a general characteristic of proteins and whether they can be applied as a valid constraint in protein structure simulations with approximated measurements (Gb-in-dex). Unexpectedly, most of the proteins showed strong structural globularity (i.e., mode of approximately 76% similarity to the perfect globe) with only a few percent of proteins being outliers. Small proteins tended to be significantly non-globular (R 2 =0.79) and the minimum Gb-index showed a logarithmic increase with the in-crease in protein size (R 2 =0.62), strongly implying that the non-globular characteristics might be more accept-able for smaller proteins than larger ones. The strong perfect globe-like character and the relationship be-tween small size and the loss of globular structure of a protein may imply that living organisms have mecha-nisms to aid folding into the globular structure to reduce irreversible aggregation. This also implies the possible mechanisms of diseases caused by protein aggregation, including some forms of trinucleotide repeat expan-sion-mediated diseases.Keywords: protein aggregation disease, protein glob-ularity, protein structure analysis

Towards a Pharmacophore for Amyloid

Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of β-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases.

Aggregation of γ-crystallins associated with human cataracts via domain swapping at the C-terminal β-strands.

The prevalent eye disease age-onset cataract is associated with aggregation of human γD-crystallins, one of the longest-lived proteins. Identification of the γ-crystallin precursors to aggregates is crucial for developing strategies to prevent and reverse cataract. Our microseconds of atomistic molecular dynamics simulations uncover the molecular structure of the experimentally detected aggregation-prone folding intermediate species of monomeric native γD-crystallin with a largely folded C-terminal domain and a mostly unfolded N-terminal domain. About 30 residues including a, b, and c strands from the Greek Key motif 4 of the C-terminal domain experience strong solvent exposure of hydrophobic residues as well as partial unstructuring upon N-terminal domain unfolding. Those strands comprise the domain-domain interface crucial for unusually high stability of γD-crystallin. We further simulate the intermolecular linkage of these monomeric aggregation precursors, which reveals domain-swapped dimeric structures. In the simulated dimeric structures, the N-terminal domain of one monomer is frequently found in contact with residues 135-164 encompassing the a, b, and c strands of the Greek Key motif 4 of the second molecule. The present results suggest that γD-crystallin may polymerize through successive domain swapping of those three C-terminal β-strands leading to age-onset cataract, as an evolutionary cost of its very high stability. Alanine substitutions of the hydrophobic residues in those aggregation-prone β-strands, such as L145 and M147, hinder domain swapping as a pathway toward dimerization. These findings thus provide critical molecular insights onto the initial stages of age-onset cataract, which is important for understanding protein aggregation diseases.

The Stability of Myocilin Olfactomedin Domain Variants Provides New Insight into Glaucoma as a Protein Misfolding Disorder

Myocilin variants, localized to the olfactomedin (OLF) domain, are linked to early-onset, inherited forms of open-angle glaucoma. Disease-causing myocilin variants accumulate within trabecular meshwork cells instead of being secreted to the trabecular extracellular matrix of the eye. We hypothesize that, like in other diseases of protein misfolding, aggregation and downstream pathogenesis originate from the compromised thermal stability of mutant myocilins. In an expansion of our pilot study of four mutants, we compare 21 additional purified OLF variants by using a fluorescence stability assay and investigate the secondary structure of the most stable variants by circular dichroism. Variants with lower melting temperatures are correlated with earlier glaucoma diagnoses. The chemical chaperone trimethylamine N-oxide is capable of restoring the stability of most, but not all, variants to wild-type (WT) levels. Interestingly, three reported OLF disease variants, A427T, G246R, and A445V, exhibited properties indistinguishable from those of WT OLF, but an increased apparent aggregation propensity in vitro relative to that of WT OLF suggests that biophysical factors other than thermal stability, such as kinetics and unfolding pathways, may also be involved in myocilin glaucoma pathogenesis. Similarly, no changes from WT OLF stability and secondary structure were detected for three annotated single-nucleotide polymorphism variants. Our work provides the first quantitative demonstration of compromised stability among many identified OLF variants and places myocilin glaucoma in the context of other diseases of protein misfolding.

Multi-Scale Sequence Correlations Increase Proteome Structural Disorder and Promiscuity

Numerous experiments demonstrate a high level of promiscuity and structural disorder in organismal proteomes. Here, we ask the question what makes a protein promiscuous, that is, prone to nonspecific interactions, and structurally disordered. We predict that multi-scale correlations of amino acid positions within protein sequences statistically enhance the propensity for promiscuous intra- and inter-protein binding. We show that sequence correlations between amino acids of the same type are statistically enhanced in structurally disordered proteins and in hubs of organismal proteomes. We also show that structurally disordered proteins possess a significantly higher degree of sequence order than structurally ordered proteins. We develop an analytical theory for this effect and predict the robustness of our conclusions with respect to the amino acid composition and the form of the microscopic potential between the interacting sequences. Our findings have implications for understanding molecular mechanisms of protein aggregation diseases induced by the extension of sequence repeats.