PDBsum entry 6d8c

Structural protein

PDB id: 6d8c

Contents

Protein chains

121 a.a.

370 a.a.

Ligands

HYP-ALA-TRP-G5G-ALA-ALO-CYS ×3

ADP ×5

Metals

_MG ×5

References listed in PDB file

Key reference

• Title: Structural basis of the filamin a actin-Binding domain interaction with f-Actin.
• Authors: D.V.Iwamoto, A.Huehn, B.Simon, C.Huet-Calderwood, M.Baldassarre, C.V.Sindelar, D.A.Calderwood.
• Ref.: Nat Struct Mol Biol, 2018, 25, 918-927. [DOI no: 10.1038/s41594-018-0128-3]
• PubMed id: 30224736

Abstract

Actin-cross-linking proteins assemble actin filaments into higher-order structures essential for orchestrating cell shape, adhesion, and motility. Missense mutations in the tandem calponin homology domains of their actin-binding domains (ABDs) underlie numerous genetic diseases, but a molecular understanding of these pathologies is hampered by the lack of high-resolution structures of any actin-cross-linking protein bound to F-actin. Here, taking advantage of a high-affinity, disease-associated mutant of the human filamin A (FLNa) ABD, we combine cryo-electron microscopy and functional studies to reveal at near-atomic resolution how the first calponin homology domain (CH1) and residues immediately N-terminal to it engage actin. We further show that reorientation of CH2 relative to CH1 is required to avoid clashes with actin and to expose F-actin-binding residues on CH1. Our data explain localization of disease-associated loss-of-function mutations to FLNaCH1 and gain-of-function mutations to the regulatory FLNaCH2. Sequence conservation argues that this provides a general model for ABD-F-actin binding.