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TitleStructural Mechanics of the Alpha-2-Macroglobulin Transformation.
Journal, issue, pagesJ Mol Biol, Vol. 434, Issue 5, Page 167413, Year 2022
Publish dateDec 20, 2021
AuthorsYasuhiro Arimura / Hironori Funabiki /
PubMed AbstractAlpha-2-Macroglobulin (A2M) is the critical pan-protease inhibitor of the innate immune system. When proteases cleave the A2M bait region, global structural transformation of the A2M tetramer is ...Alpha-2-Macroglobulin (A2M) is the critical pan-protease inhibitor of the innate immune system. When proteases cleave the A2M bait region, global structural transformation of the A2M tetramer is triggered to entrap the protease. The structural basis behind the cleavage-induced transformation and the protease entrapment remains unclear. Here, we report cryo-EM structures of native- and intermediate-forms of the Xenopus laevis egg A2M homolog (A2Moo or ovomacroglobulin) tetramer at 3.7-4.1 Å and 6.4 Å resolution, respectively. In the native A2Moo tetramer, two pairs of dimers arrange into a cross-like configuration with four 60 Å-wide bait-exposing grooves. Each bait in the native form threads into an aperture formed by three macroglobulin domains (MG2, MG3, MG6). The bait is released from the narrowed aperture in the induced protomer of the intermediate form. We propose that the intact bait region works as a "latch-lock" to block futile A2M transformation until its protease-mediated cleavage.
External linksJ Mol Biol / PubMed:34942166 / PubMed Central
MethodsEM (single particle)
Resolution3.65 - 6.43 Å
Structure data

EMDB-24847, PDB-7s62:
Locally refined protomer structure of native-form oocyte/egg Alpha-2-Macroglobulin (A2Moo) tetramer
Method: EM (single particle) / Resolution: 3.65 Å

EMDB-24848, PDB-7s63:
Native-form oocyte/egg Alpha-2-Macroglobulin (A2Moo) tetramer
Method: EM (single particle) / Resolution: 4.12 Å

EMDB-24849, PDB-7s64:
Intermediate-form oocyte/egg Alpha-2-Macroglobulin (A2Moo) tetramer
Method: EM (single particle) / Resolution: 6.43 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • xenopus laevis (African clawed frog)
  • African clawed frog (African clawed frog)
KeywordsPROTEIN BINDING / Xenopus egg extract / Protease inhibitor

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