9rwf | pdb_00009rwf

Solution NMR structure of a peptide encompassing residues 967-991 of the human formin INF2

spinqualitylabelsall models 9rwf Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9rwf is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, models Ligands: ACE, NH2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease INF2_HUMAN Autosomal dominant intermediate Charcot-Marie-Tooth disease type E;Genetic steroid-resistant nephrotic syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Function INF2_HUMAN Severs actin filaments and accelerates their polymerization and depolymerization. Publication Abstract from PubMed Inverted formin-2 (INF2), a formin linked to inherited renal and neurological disorders, exhibits pathogenic variants that lead to deregulated actin polymerization and nuclear aberrations, ultimately compromising cell viability. Most formins contain a diaphanous autoregulatory domain (DAD) and a diaphanous inhibitory domain (DID), which interact to keep the molecule in an inactive state. The DAD consists of a short sequence with an N-terminal region rich in hydrophobic residues and a C-terminal segment abundant in basic residues, resembling WASP homology 2 (WH2) actin-binding domains. Based on its sequence and actin-binding ability, the DAD of INF2 qualifies as a WH2 motif. In this study, we investigated the structure of the INF2 WH2/DAD by nuclear magnetic resonance (NMR) and explored its functional role. Our analysis revealed that the WH2/DAD forms a single alpha-helix in both H(2)O and 30% 2,2,2-trifluoroethanol that differs from the conformations observed in WH2-actin and DAD-DID crystal structures. Cells expressing INF2 containing only the hydrophobic region of the WH2/DAD exhibited higher F-actin levels and frequencies of nuclear abnormalities, phenocopying the effect of pathogenic INF2 DID variants. In contrast, deletion of the entire WH2/DAD, or of the hydrophobic region alone, abolishes INF2 activity. Neither these deletions nor WH2/DAD variants carrying naturally occurring missense mutations induced any detectable nuclear effects. These findings suggest that the WH2/DAD undergoes a conformational change to facilitate actin binding and that the hydrophobic region is essential for INF2-mediated actin polymerization. INF2 WH2/DAD variants with deleterious cellular effects appear to be rare in, or absent from, the human population. Structural and functional dissection of the WH2/DAD motif of INF2, a formin linked to human inherited degenerative disorders.,Labat-de-Hoz L, Fernandez-Martin L, Morales P, Correas I, Jimenez MA, Alonso MA FEBS J. 2025 Sep 24. doi: 10.1111/febs.70271. PMID:40993919 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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