3SUI

Crystal structure of ca2+-calmodulin in complex with a trpv1 c-terminal peptide

Summary for 3SUI

• Entry DOI: 10.2210/pdb3sui/pdb
• Descriptor: Calmodulin, Transient receptor potential cation channel subfamily V member 1, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: calmodulin, calcium-calmodulin, trpv1, trpv1 c-terminus, calmodulin complex, thermosensor, trp channel, ef hands, 1-10 motif, calcium channel, calmodulin-binding, ion channel, calcium binding protein, calcium-binding protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cell junction, synapse, postsynaptic cell membrane ; Multi-pass membrane protein : O35433
• Total number of polymer chains: 2
• Total formula weight: 21189.60

Authors

Lau, S.-Y.,Gaudet, R. (deposition date: 2011-07-11, release date: 2012-09-12, Last modification date: 2023-09-13)

Primary citation

Lau, S.Y.,Procko, E.,Gaudet, R.
Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel.
J.Gen.Physiol., 140:541-555, 2012

PubMed Abstract: Transient receptor potential (TRP) vanilloid 1 (TRPV1) is a molecular pain receptor belonging to the TRP superfamily of nonselective cation channels. As a polymodal receptor, TRPV1 responds to heat and a wide range of chemical stimuli. The influx of calcium after channel activation serves as a negative feedback mechanism leading to TRPV1 desensitization. The cellular calcium sensor calmodulin (CaM) likely participates in the desensitization of TRPV1. Two CaM-binding sites are identified in TRPV1: the N-terminal ankyrin repeat domain (ARD) and a short distal C-terminal (CT) segment. Here, we present the crystal structure of calcium-bound CaM (Ca(2+)-CaM) in complex with the TRPV1-CT segment, determined to 1.95-Å resolution. The two lobes of Ca(2+)-CaM wrap around a helical TRPV1-CT segment in an antiparallel orientation, and two hydrophobic anchors, W787 and L796, contact the C-lobe and N-lobe of Ca(2+)-CaM, respectively. This structure is similar to canonical Ca(2+)-CaM-peptide complexes, although TRPV1 contains no classical CaM recognition sequence motif. Using structural and mutational studies, we established the TRPV1 C terminus as a high affinity Ca(2+)-CaM-binding site in both the isolated TRPV1 C terminus and in full-length TRPV1. Although a ternary complex of CaM, TRPV1-ARD, and TRPV1-CT had previously been postulated, we found no biochemical evidence of such a complex. In electrophysiology studies, mutation of the Ca(2+)-CaM-binding site on TRPV1-ARD abolished desensitization in response to repeated application of capsaicin, whereas mutation of the Ca(2+)-CaM-binding site in TRPV1-CT led to a more subtle phenotype of slowed and reduced TRPV1 desensitization. In summary, our results show that the TRPV1-ARD is an important mediator of TRPV1 desensitization, whereas TRPV1-CT has higher affinity for CaM and is likely involved in separate regulatory mechanisms.

PubMed: 23109716
DOI: 10.1085/jgp.201210810

Experimental method

X-RAY DIFFRACTION (1.95 Å)