A human infertility-associated KASH5 variant promotes mitochondrial localization

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 ch...

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Autores principales:	Sana A. Bentebbal, Bakhita R. Meqbel, Anna Salter, Victoria Allan, Brian Burke, Henning F. Horn
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/72fa3c2c2c9744ac981eee51f3025ab0
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spelling	oai:doaj.org-article:72fa3c2c2c9744ac981eee51f3025ab02021-12-02T15:43:08ZA human infertility-associated KASH5 variant promotes mitochondrial localization10.1038/s41598-021-89439-22045-2322https://doaj.org/article/72fa3c2c2c9744ac981eee51f3025ab02021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89439-2https://doaj.org/toc/2045-2322Abstract 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.Sana A. BentebbalBakhita R. MeqbelAnna SalterVictoria AllanBrian BurkeHenning F. HornNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sana A. Bentebbal Bakhita R. Meqbel Anna Salter Victoria Allan Brian Burke Henning F. Horn A human infertility-associated KASH5 variant promotes mitochondrial localization
description	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.
format	article
author	Sana A. Bentebbal Bakhita R. Meqbel Anna Salter Victoria Allan Brian Burke Henning F. Horn
author_facet	Sana A. Bentebbal Bakhita R. Meqbel Anna Salter Victoria Allan Brian Burke Henning F. Horn
author_sort	Sana A. Bentebbal
title	A human infertility-associated KASH5 variant promotes mitochondrial localization
title_short	A human infertility-associated KASH5 variant promotes mitochondrial localization
title_full	A human infertility-associated KASH5 variant promotes mitochondrial localization
title_fullStr	A human infertility-associated KASH5 variant promotes mitochondrial localization
title_full_unstemmed	A human infertility-associated KASH5 variant promotes mitochondrial localization
title_sort	human infertility-associated kash5 variant promotes mitochondrial localization
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/72fa3c2c2c9744ac981eee51f3025ab0
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A human infertility-associated KASH5 variant promotes mitochondrial localization

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