9H75

NMR solution structure of the GEFH1 C1 domain

Summary for 9H75

• Entry DOI: 10.2210/pdb9h75/pdb
• NMR Information: BMRB: 34965
• Descriptor: Rho guanine nucleotide exchange factor 2, ZINC ION (2 entities in total)
• Functional Keywords: structure from cyana 3.98.4, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 8381.57

Authors

Choi, S.R.,Gossert, A.D.,Steinmetz, M.O. (deposition date: 2024-10-26, release date: 2025-11-05, Last modification date: 2026-01-14)

Primary citation

Choi, S.R.,Blum, T.B.,Giono, M.,Roy, B.,Vakonakis, I.,Schmid, D.,Oelgarth, N.,Ranganathan, A.,Gossert, A.D.,Shivashankar, G.V.,Zippelius, A.,Steinmetz, M.O.
Structural basis of microtubule-mediated signal transduction.
Cell, 2025

PubMed Abstract: Microtubules have long been recognized as upstream mediators of intracellular signaling, but the mechanisms underlying this fundamental function remain elusive. Here, we identify the structural basis by which microtubules regulate the guanine nucleotide exchange factor H1 (GEFH1), a key activator of the Ras homolog family member A (RhoA) pathway. We show that specific features of the microtubule lattice bind the C1 domain of GEFH1, leading to the sequestration and inactivation of this signaling protein. Targeted mutations in C1 residues disrupt this interaction, triggering GEFH1 release and activation of RhoA-dependent immune responses. Building on this sequestration-and-release mechanism, we identify microtubule-binding C1 domains in additional signaling proteins, including other guanine nucleotide exchange factors (GEFs), kinases, a GTPase-activating protein (GAP), and a tumor suppressor, and show that microtubule-mediated regulation via C1 domains is conserved in the Ras association domain-containing protein 1A (RASSF1A). Our findings establish a structural framework for understanding how microtubules can function as spatiotemporal signal sensors, integrating and processing diverse signaling pathways to control important cellular processes.

PubMed: 41365297
DOI: 10.1016/j.cell.2025.11.011

Experimental method

SOLUTION NMR