6BUT

Solution structure of full-length apo mammalian calmodulin bound to the IQ motif of the human voltage-gated sodium channel NaV1.2

Summary for 6BUT

• Entry DOI: 10.2210/pdb6but/pdb
• NMR Information: BMRB: 27095
• Descriptor: Calmodulin-1, Sodium channel protein type 2 subunit alpha (2 entities in total)
• Functional Keywords: calcium-binding protein, metal transport ion channel neuronal molecular recognition, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 20403.76

Authors

Mahling, R.,Kilpatrick, A.M.,Shea, M.A. (deposition date: 2017-12-11, release date: 2019-06-19, Last modification date: 2024-05-01)

Primary citation

Mahling, R.,Hovey, L.,Isbell, H.M.,Marx, D.C.,Miller, M.S.,Kilpatrick, A.M.,Weaver, L.D.,Yoder, J.B.,Kim, E.H.,Andresen, C.N.J.,Li, S.,Shea, M.A.
Na V 1.2 EFL domain allosterically enhances Ca 2+ binding to sites I and II of WT and pathogenic calmodulin mutants bound to the channel CTD.
Structure, 2021

PubMed Abstract: Neuronal voltage-gated sodium channel Na1.2 C-terminal domain (CTD) binds calmodulin (CaM) constitutively at its IQ motif. A solution structure (6BUT) and other NMR evidence showed that the CaM N domain (CaM) is structurally independent of the C-domain (CaM) whether CaM is bound to the Na1.2 (1,901-1,927) or Na1.2 (1,777-1,937) with or without calcium. However, in the CaM + Na1.2 complex, the Ca affinity of CaM was more favorable than in free CaM, while Ca affinity for CaM was weaker than in the CaM + Na1.2 complex. The CTD EF-like (EFL) domain allosterically widened the energetic gap between CaM domains. Cardiomyopathy-associated CaM mutants (N53I(N54I), D95V(D96V), A102V(A103V), E104A(E105A), D129G(D130G), and F141L(F142L)) all bound the Na1.2 IQ motif favorably under resting (apo) conditions and bound calcium normally at CaM sites. However, only N53I and A102V bound calcium at CaM sites at [Ca] < 100 μM. Thus, they are expected to respond like wild-type CaM to Ca spikes in excitable cells.

PubMed: 33770503
DOI: 10.1016/j.str.2021.03.002

Experimental method

SOLUTION NMR