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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...

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Autores principales: 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.
Formato: Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2010
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.
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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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