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Cryogenic electron microscopy 3D map of F-actin bound by the Actin Binding Domain of alpha-catenin ortholog, HMP1Cryogenic electron microscopy 3D map of F-actin bound by the Actin Binding Domain of alpha-catenin ortholog, HMP1
Structural highlights
FunctionACTS_RABIT Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells. Publication Abstract from PubMedThe regulation of cell-cell junctions during epidermal morphogenesis ensures tissue integrity, a process regulated by alpha-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 alpha-catenin that functions as a dimer or monomer, the alpha-catenin ortholog from C. elegans, HMP1 for humpback, is a monomer. Our cryogenic electron microscopy (cryoEM) structure of HMP1/alpha-catenin reveals that the amino- and carboxy-terminal domains of HMP1/alpha-catenin are disordered and not in contact with the remaining HMP1/alpha-catenin middle domain. Since the carboxy-terminal HMP1/alpha-catenin domain is the F-actin-binding domain (FABD), this interdomain constellation suggests that HMP1/alpha-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/alpha-catenin bound to F-actin. Unlike the structure of mammalian alpha-catenin bound to F-actin, binding to F-actin seems to allosterically convert a loop region of the HMP1/alpha-catenin FABD to extend an HMP1/alpha-catenin FABD alpha-helix. We use cryoEM and bundling assays to show for the first time how the FABD of HMP1/alpha-catenin bundles actin in the absence of force. Collectively, our data advance our understanding of alpha-catenin regulation of cell-cell contacts and additionally aid our understanding of the evolution of multicellularity in metazoans. The nematode alpha-catenin ortholog, HMP1, has an extended alpha-helix when bound to actin filaments.,Rangarajan ES, Smith EW, Izard T J Biol Chem. 2022 Dec 17;299(2):102817. doi: 10.1016/j.jbc.2022.102817. PMID:36539037[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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