6GDL

Calmodulin mutant - F141L apo-form Unstructured C-domain

Summary for 6GDL

• Entry DOI: 10.2210/pdb6gdl/pdb
• NMR Information: BMRB: 34263
• Descriptor: Calmodulin-1 (1 entity in total)
• Functional Keywords: calmodulin, signaling protein, calcium signalling
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 16687.33

Authors

Holt, C.,Overgaard, M.T.,Wimmer, R. (deposition date: 2018-04-23, release date: 2018-10-17, Last modification date: 2024-05-15)

Primary citation

Wang, K.,Holt, C.,Lu, J.,Brohus, M.,Larsen, K.T.,Overgaard, M.T.,Wimmer, R.,Van Petegem, F.
Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel.
Proc. Natl. Acad. Sci. U.S.A., 115:E10556-E10565, 2018

PubMed Abstract: Calmodulin (CaM) represents one of the most conserved proteins among eukaryotes and is known to bind and modulate more than a 100 targets. Recently, several disease-associated mutations have been identified in the genes that are causative of severe cardiac arrhythmia syndromes. Although several mutations have been shown to affect the function of various cardiac ion channels, direct structural insights into any CaM disease mutation have been lacking. Here we report a crystallographic and NMR investigation of several disease mutant CaMs, linked to long-QT syndrome, in complex with the IQ domain of the cardiac voltage-gated calcium channel (Ca1.2). Surprisingly, two mutants (D95V, N97I) cause a major distortion of the C-terminal lobe, resulting in a pathological conformation not reported before. These structural changes result in altered interactions with the Ca1.2 IQ domain. Another mutation (N97S) reduces the affinity for Ca by introducing strain in EF hand 3. A fourth mutant (F141L) shows structural changes in the Ca-free state that increase the affinity for the IQ domain. These results thus show that different mechanisms underlie the ability of CaM disease mutations to affect Ca-dependent inactivation of the voltage-gated calcium channel.

PubMed: 30348784
DOI: 10.1073/pnas.1808733115

Experimental method

SOLUTION NMR