9RWF

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

Summary for 9RWF

• Entry DOI: 10.2210/pdb9rwf/pdb
• Related: 9G7T
• NMR Information: BMRB: 52961
• Descriptor: Inverted formin-2 (1 entity in total)
• Functional Keywords: formins, actin, microtubules, inherited disease, cell adhesion
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 2886.35

Authors

Jimenez, M.A.,Morales, P.,Correas, I.,Alonso, M.A. (deposition date: 2025-07-09, release date: 2025-10-08, Last modification date: 2026-02-18)

Primary citation

Labat-de-Hoz, L.,Fernandez-Martin, L.,Morales, P.,Correas, I.,Jimenez, M.A.,Alonso, M.A.
Structural and functional dissection of the WH2/DAD motif of INF2, a formin linked to human inherited degenerative disorders.
Febs J., 293:825-841, 2026

PubMed Abstract: 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 α-helix in both HO 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.

PubMed: 40993919
DOI: 10.1111/febs.70271

Experimental method

SOLUTION NMR