Abstract
KASH5 is the most recently identified member of the KASH domain family of tail anchored, outer nuclear membrane (ONM) and endoplasmic reticulum (ER) proteins. During meiosis prophase I, KASH5 and SUN1 form a complex that spans the nuclear envelope and which links the telomeres of meiotic chromosomes to cytoplasmic dynein. This connection is essential for homologous chromosome dynamics and pairing. A recent study identified a variant in human KASH5 (L535Q) that correlated with male infertility associated with azoospermia. However, no molecular mechanism was described. Here, we report that this amino acid substitution, within the KASH5 transmembrane domain (TMD) has no predicted effects on secondary structure. However, the overall hydrophobicity of the L535Q TMD, is calculated to be lower than the wild-type KASH5, based on the GES (Goldman–Engelman–Steitz) amino acid hydrophobicity scale. This change in hydrophobicity profoundly affects the subcellular localization of KASH5. Through a series of amino acid substitution studies, we show that the L535Q substitution perturbs KASH5 localization to the ER and ONM and instead results in mistargeting to the mitochondria membrane. We suggest that this mislocalization accounts for the infertility and azoospermia phenotype in patients.
Highlights
The nuclear envelope (NE) is a defining feature of eukaryotic cells
To understand the effects of this substitution we compared the predicted secondary structure (I-TASSER, University of Michigan) of the transmembrane domain (TMD) for both the wild-type and L535Q variant KASH5 proteins. These analyses indicated that the L535Q substitution is not expected to perturb the alpha-helical structure of the KASH5 TMD (Fig. 1A)
Homologous pairing is achieved through chromosomal movements coupled with nuclear rotations, both of which occur in prophase I of meiosis and are referred to as rapid prophase movements (RPM)
Summary
The nuclear envelope (NE) is a defining feature of eukaryotic cells. By separating the genome from the cytoplasm, the NE establishes the boundary of the nucleus. Beyond its role as a physical barrier, the NE has a pivotal role in various cellular functions including signaling pathway, transcriptional regulation, chromatin and cytoskeleton organization[2] All these functions are mediated by an array of protein complexes present on both INM and/or ONM. The mammalian SUN family members all share a common topology Their N-terminal domain resides in the nucleoplasm where it tethers nuclear structures to the INM, while their C-terminal segment, containing the highly conserved SUN domain (~ 175 residues), extends into the PNS where it engages with KASH family m embers[11]. Six members of the mammalian KASH domain family of tail-anchored transmembrane proteins have been identified to date These include Nesprin (nuclear envelope spectrin repeat domain)-1, -2, -3 and -4, KASH5 and Scientific Reports | (2021) 11:10133. This larger complex could explain how the LINC complex provides for maximal forces transfer across the N E13
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
