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Bardet-Biedl Syndrome-associated Small GTPase ARL6 (BBS3) Functions at or near the Ciliary Gate and Modulates Wnt Signaling
The expansive family of metazoan ADP-ribosylation factor and ADP-ribosylation factor-like small GTPases is known to play essential roles in modulating membrane trafficking and cytoskeletal functions. Here, we present the crystal structure of ARL6, mutations in which cause Bardet-Biedl syndrome (BBS3...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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American Society for Biochemistry and Molecular Biology
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871489/ https://www.ncbi.nlm.nih.gov/pubmed/20207729 http://dx.doi.org/10.1074/jbc.M109.070953 |
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author | Wiens, Cheryl J. Tong, Yufeng Esmail, Muneer A. Oh, Edwin Gerdes, Jantje M. Wang, Jihong Tempel, Wolfram Rattner, Jerome B. Katsanis, Nicholas Park, Hee-Won Leroux, Michel R. |
author_facet | Wiens, Cheryl J. Tong, Yufeng Esmail, Muneer A. Oh, Edwin Gerdes, Jantje M. Wang, Jihong Tempel, Wolfram Rattner, Jerome B. Katsanis, Nicholas Park, Hee-Won Leroux, Michel R. |
author_sort | Wiens, Cheryl J. |
collection | PubMed |
description | The expansive family of metazoan ADP-ribosylation factor and ADP-ribosylation factor-like small GTPases is known to play essential roles in modulating membrane trafficking and cytoskeletal functions. Here, we present the crystal structure of ARL6, mutations in which cause Bardet-Biedl syndrome (BBS3), and reveal its unique ring-like localization at the distal end of basal bodies, in proximity to the so-called ciliary gate where vesicles carrying ciliary cargo fuse with the membrane. Overproduction of GDP- or GTP-locked variants of ARL6/BBS3 in vivo influences primary cilium length and abundance. ARL6/BBS3 also modulates Wnt signaling, a signal transduction pathway whose association with cilia in vertebrates is just emerging. Importantly, this signaling function is lost in ARL6 variants containing BBS-associated point mutations. By determining the structure of GTP-bound ARL6/BBS3, coupled with functional assays, we provide a mechanistic explanation for such pathogenic alterations, namely altered nucleotide binding. Our findings therefore establish a previously unknown role for ARL6/BBS3 in mammalian ciliary (dis)assembly and Wnt signaling and provide the first structural information for a BBS protein. |
format | Text |
id | pubmed-2871489 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-28714892010-05-18 Bardet-Biedl Syndrome-associated Small GTPase ARL6 (BBS3) Functions at or near the Ciliary Gate and Modulates Wnt Signaling Wiens, Cheryl J. Tong, Yufeng Esmail, Muneer A. Oh, Edwin Gerdes, Jantje M. Wang, Jihong Tempel, Wolfram Rattner, Jerome B. Katsanis, Nicholas Park, Hee-Won Leroux, Michel R. J Biol Chem Molecular Bases of Disease The expansive family of metazoan ADP-ribosylation factor and ADP-ribosylation factor-like small GTPases is known to play essential roles in modulating membrane trafficking and cytoskeletal functions. Here, we present the crystal structure of ARL6, mutations in which cause Bardet-Biedl syndrome (BBS3), and reveal its unique ring-like localization at the distal end of basal bodies, in proximity to the so-called ciliary gate where vesicles carrying ciliary cargo fuse with the membrane. Overproduction of GDP- or GTP-locked variants of ARL6/BBS3 in vivo influences primary cilium length and abundance. ARL6/BBS3 also modulates Wnt signaling, a signal transduction pathway whose association with cilia in vertebrates is just emerging. Importantly, this signaling function is lost in ARL6 variants containing BBS-associated point mutations. By determining the structure of GTP-bound ARL6/BBS3, coupled with functional assays, we provide a mechanistic explanation for such pathogenic alterations, namely altered nucleotide binding. Our findings therefore establish a previously unknown role for ARL6/BBS3 in mammalian ciliary (dis)assembly and Wnt signaling and provide the first structural information for a BBS protein. American Society for Biochemistry and Molecular Biology 2010-05-21 2010-03-05 /pmc/articles/PMC2871489/ /pubmed/20207729 http://dx.doi.org/10.1074/jbc.M109.070953 Text en © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles |
spellingShingle | Molecular Bases of Disease Wiens, Cheryl J. Tong, Yufeng Esmail, Muneer A. Oh, Edwin Gerdes, Jantje M. Wang, Jihong Tempel, Wolfram Rattner, Jerome B. Katsanis, Nicholas Park, Hee-Won Leroux, Michel R. Bardet-Biedl Syndrome-associated Small GTPase ARL6 (BBS3) Functions at or near the Ciliary Gate and Modulates Wnt Signaling |
title | Bardet-Biedl Syndrome-associated Small GTPase ARL6 (BBS3) Functions at or near the Ciliary Gate and Modulates Wnt Signaling |
title_full | Bardet-Biedl Syndrome-associated Small GTPase ARL6 (BBS3) Functions at or near the Ciliary Gate and Modulates Wnt Signaling |
title_fullStr | Bardet-Biedl Syndrome-associated Small GTPase ARL6 (BBS3) Functions at or near the Ciliary Gate and Modulates Wnt Signaling |
title_full_unstemmed | Bardet-Biedl Syndrome-associated Small GTPase ARL6 (BBS3) Functions at or near the Ciliary Gate and Modulates Wnt Signaling |
title_short | Bardet-Biedl Syndrome-associated Small GTPase ARL6 (BBS3) Functions at or near the Ciliary Gate and Modulates Wnt Signaling |
title_sort | bardet-biedl syndrome-associated small gtpase arl6 (bbs3) functions at or near the ciliary gate and modulates wnt signaling |
topic | Molecular Bases of Disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871489/ https://www.ncbi.nlm.nih.gov/pubmed/20207729 http://dx.doi.org/10.1074/jbc.M109.070953 |
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