31DM

Holo form of calmodulin-like domain of human alpha-actinin-4

Summary for 31DM

• Entry DOI: 10.2210/pdb31dm/pdb
• NMR Information: BMRB: 53778
• Descriptor: Alpha-actinin-4, CALCIUM ION (2 entities in total)
• Functional Keywords: calcium-binding protein, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 17027.73

Authors

Hocevar, J.,Kovacic, M.,Plavec, J.,Djinovic-Carugo, K.,Pavsic, M. (deposition date: 2026-05-27, release date: 2026-10-21, Last modification date: 2026-11-04)

Primary citation

Hocevar, J.,Kovacic, M.,Plavec, J.,Djinovic-Carugo, K.,Pavsic, M.
Distinct Ca 2+ -binding thermodynamics reveal a paralogue-specific structural response in the calmodulin-like domain of alpha-actinin-4.
Int.J.Biol.Macromol., 384:154866-154866, 2026

PubMed Abstract: The actin cytoskeleton, a complex and dynamic network, is precisely organized into structurally and functionally diverse assemblies by actin-binding proteins. A major group of actin crosslinking proteins are α-actinins. The non-muscle forms, α-actinin-1 and -4, are ubiquitous proteins whose actin crosslinking activity is regulated by Ca ions. The molecular mechanism of regulation is unknown, but it has been suggested to be driven by structural changes triggered by the binding of Ca ions to their calmodulin-like domain (CaMD). While the structure and Ca-binding properties of human α-actinin-1 CaMD have already been investigated, no such data were available for the α-actinin-4 CaMD. To address this, we used structurally informed mutagenesis and isothermal titration calorimetry (ITC) to confirm a homologous single Ca-binding site in the N-terminal lobe of the α-actinin-4 CaMD. In stark contrast to the α-actinin-1 CaMD, where binding is endothermic, binding to the α-actinin-4 CaMD is exothermic and displays a 6-fold lower affinity towards Ca. These distinct thermodynamic signatures suggest a paralogue-specific conformational change. Indeed, protein NMR spectroscopy revealed a unique Ca-induced conformational change of the C-terminal lobe, providing new insights into the molecular mechanisms that modulate α-actinin-mediated actin crosslinking.

PubMed: 42874945
DOI: 10.1016/j.ijbiomac.2026.154866

Experimental method

SOLUTION NMR