Cargando…

A Method to Find Longevity-Selected Positions in the Mammalian Proteome

Evolutionary theory suggests that the force of natural selection decreases with age. To explore the extent to which this prediction directly affects protein structure and function, we used multiple regression to find longevity-selected positions, defined as the columns of a sequence alignment conser...

Descripción completa

Detalles Bibliográficos
Autores principales: Semeiks, Jeremy, Grishin, Nick V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372525/
https://www.ncbi.nlm.nih.gov/pubmed/22701678
http://dx.doi.org/10.1371/journal.pone.0038595
_version_ 1782235363568254976
author Semeiks, Jeremy
Grishin, Nick V.
author_facet Semeiks, Jeremy
Grishin, Nick V.
author_sort Semeiks, Jeremy
collection PubMed
description Evolutionary theory suggests that the force of natural selection decreases with age. To explore the extent to which this prediction directly affects protein structure and function, we used multiple regression to find longevity-selected positions, defined as the columns of a sequence alignment conserved in long-lived but not short-lived mammal species. We analyzed 7,590 orthologous protein families in 33 mammalian species, accounting for body mass, phylogeny, and species-specific mutation rate. Overall, we found that the number of longevity-selected positions in the mammalian proteome is much higher than would be expected by chance. Further, these positions are enriched in domains of several proteins that interact with one another in inflammation and other aging-related processes, as well as in organismal development. We present as an example the kinase domain of anti-Müllerian hormone type-2 receptor (AMHR2). AMHR2 inhibits ovarian follicle recruitment and growth, and a homology model of the kinase domain shows that its longevity-selected positions cluster near a SNP associated with delayed human menopause. Distinct from its canonical role in development, this region of AMHR2 may function to regulate the protein’s activity in a lifespan-specific manner.
format Online
Article
Text
id pubmed-3372525
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-33725252012-06-13 A Method to Find Longevity-Selected Positions in the Mammalian Proteome Semeiks, Jeremy Grishin, Nick V. PLoS One Research Article Evolutionary theory suggests that the force of natural selection decreases with age. To explore the extent to which this prediction directly affects protein structure and function, we used multiple regression to find longevity-selected positions, defined as the columns of a sequence alignment conserved in long-lived but not short-lived mammal species. We analyzed 7,590 orthologous protein families in 33 mammalian species, accounting for body mass, phylogeny, and species-specific mutation rate. Overall, we found that the number of longevity-selected positions in the mammalian proteome is much higher than would be expected by chance. Further, these positions are enriched in domains of several proteins that interact with one another in inflammation and other aging-related processes, as well as in organismal development. We present as an example the kinase domain of anti-Müllerian hormone type-2 receptor (AMHR2). AMHR2 inhibits ovarian follicle recruitment and growth, and a homology model of the kinase domain shows that its longevity-selected positions cluster near a SNP associated with delayed human menopause. Distinct from its canonical role in development, this region of AMHR2 may function to regulate the protein’s activity in a lifespan-specific manner. Public Library of Science 2012-06-11 /pmc/articles/PMC3372525/ /pubmed/22701678 http://dx.doi.org/10.1371/journal.pone.0038595 Text en Semeiks, Grishin. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Semeiks, Jeremy
Grishin, Nick V.
A Method to Find Longevity-Selected Positions in the Mammalian Proteome
title A Method to Find Longevity-Selected Positions in the Mammalian Proteome
title_full A Method to Find Longevity-Selected Positions in the Mammalian Proteome
title_fullStr A Method to Find Longevity-Selected Positions in the Mammalian Proteome
title_full_unstemmed A Method to Find Longevity-Selected Positions in the Mammalian Proteome
title_short A Method to Find Longevity-Selected Positions in the Mammalian Proteome
title_sort method to find longevity-selected positions in the mammalian proteome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372525/
https://www.ncbi.nlm.nih.gov/pubmed/22701678
http://dx.doi.org/10.1371/journal.pone.0038595
work_keys_str_mv AT semeiksjeremy amethodtofindlongevityselectedpositionsinthemammalianproteome
AT grishinnickv amethodtofindlongevityselectedpositionsinthemammalianproteome
AT semeiksjeremy methodtofindlongevityselectedpositionsinthemammalianproteome
AT grishinnickv methodtofindlongevityselectedpositionsinthemammalianproteome