Mechanistic basis for calmodulin‑dependent allosteric activation of the neuropathy-associated formin INF2.

Authors

Bohan Zhang, Meng Zhang, Ke Liu, Chenhui Zhao, Jianwen Zhang, Zhijun Liu, Ying Fan, Ruo-Xu Gu, Lin Lin, Chuanhai Fu, Jinwei Zhu

Published in

Cell reports. Volume 45. Issue 8. Pages 117750. Aug 03, 2026. Epub Aug 03, 2026.

Abstract

Calcium signaling regulates the atypical formin INF2 to drive actin assembly in diverse cellular processes, yet the underlying molecular mechanism remains elusive. Here, we uncover a direct, nanomolar-affinity interaction between calcium-bound calmodulin (Ca²⁺-CaM) and the diaphanous inhibitory domain (DID) of INF2. The high-resolution crystal structure of the Ca²⁺-CaM-INF2 DID complex reveals a unique allosteric activation mechanism distinct from canonical Rho GTPase-mediated formin regulation. Ca²⁺-CaM binding induces conformational changes that disrupt the autoinhibitory DID-DAD interaction, triggering its actin assembly activity. We show that Ca²⁺-CaM activates ER-bound INF2, thereby promoting mitochondrial fission. We further demonstrate that a Charcot-Marie-Tooth neuropathy-associated INF2 mutation enhances Ca²⁺-CaM binding through optimized interfacial dynamics, revealing a gain-of-function disease mechanism. Our findings provide a mechanistic framework for Ca²⁺-CaM-dependent activation of INF2, establishing the CaM-INF2 axis as a direct activator of actin-dependent organelle dynamics, with implications for INF2-linked pathologies.

PMID:
42545850
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.

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