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The nematode α-catenin ortholog, HMP1, has an extended α-helix when bound to actin filaments.
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- Author(s): Rangarajan ES;Rangarajan ES; Smith EW; Smith EW; Izard T; Izard T; Izard T
- Source:
The Journal of biological chemistry [J Biol Chem] 2023 Feb; Vol. 299 (2), pp. 102817. Date of Electronic Publication: 2022 Dec 17.
- Publication Type:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
- Language:
English
- Additional Information
- Source:
Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
- Publication Information:
Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
- Subject Terms:
- Abstract:
The regulation of cell-cell junctions during epidermal morphogenesis ensures tissue integrity, a process regulated by α-catenin. This cytoskeletal protein connects the cadherin complex to filamentous actin at cell-cell junctions. The cadherin-catenin complex plays key roles in cell physiology, organism development, and disease. While mutagenesis of Caenorhabditis elegans cadherin and catenin shows that these proteins are key for embryonic morphogenesis, we know surprisingly little about their structure and attachment to the cytoskeleton. In contrast to mammalian α-catenin that functions as a dimer or monomer, the α-catenin ortholog from C. elegans, HMP1 for humpback, is a monomer. Our cryogenic electron microscopy (cryoEM) structure of HMP1/α-catenin reveals that the amino- and carboxy-terminal domains of HMP1/α-catenin are disordered and not in contact with the remaining HMP1/α-catenin middle domain. Since the carboxy-terminal HMP1/α-catenin domain is the F-actin-binding domain (FABD), this interdomain constellation suggests that HMP1/α-catenin is constitutively active, which we confirm biochemically. Our perhaps most surprising finding, given the high sequence similarity between the mammalian and nematode proteins, is our cryoEM structure of HMP1/α-catenin bound to F-actin. Unlike the structure of mammalian α-catenin bound to F-actin, binding to F-actin seems to allosterically convert a loop region of the HMP1/α-catenin FABD to extend an HMP1/α-catenin FABD α-helix. We use cryoEM and bundling assays to show for the first time how the FABD of HMP1/α-catenin bundles actin in the absence of force. Collectively, our data advance our understanding of α-catenin regulation of cell-cell contacts and additionally aid our understanding of the evolution of multicellularity in metazoans.
Competing Interests: Conflict of interest The authors declare no conflict of interest with the contents of this article.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Grant Information:
R35 GM139604 United States GM NIGMS NIH HHS
- Contributed Indexing:
Keywords: actin; cancer; cell adhesion; cell junction; cell migration; cell signaling
- Accession Number:
0 (Actins)
0 (alpha Catenin)
0 (Cadherins)
0 (HMP-1 protein, C elegans)
- Publication Date:
Date Created: 20221220 Date Completed: 20230301 Latest Revision: 20240425
- Publication Date:
20240425
- Accession Number:
PMC9860117
- Accession Number:
10.1016/j.jbc.2022.102817
- Accession Number:
36539037
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