Abstract
In heart and skeletal muscle an S100 protein family member, S100A1, binds to the ryanodine receptor (RyR) and promotes Ca(2+) release. Using competition binding assays, we further characterized this system in skeletal muscle and showed that Ca(2+)-S100A1 competes with Ca(2+)-calmodulin (CaM) for the same binding site on RyR1. In addition, the NMR structure was determined for Ca(2+)-S100A1 bound to a peptide derived from this CaM/S100A1 binding domain, a region conserved in RyR1 and RyR2 and termed RyRP12 (residues 3616-3627 in human RyR1). Examination of the S100A1-RyRP12 complex revealed residues of the helical RyRP12 peptide (Lys-3616, Trp-3620, Lys-3622, Leu-3623, Leu-3624, and Lys-3626) that are involved in favorable hydrophobic and electrostatic interactions with Ca(2+)-S100A1. These same residues were shown previously to be important for RyR1 binding to Ca(2+)-CaM. A model for regulating muscle contraction is presented in which Ca(2+)-S100A1 and Ca(2+)-CaM compete directly for the same binding site on the ryanodine receptor.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Binding Sites / physiology
-
Calcium / chemistry
-
Calcium / metabolism*
-
Calmodulin / chemistry
-
Calmodulin / genetics
-
Calmodulin / metabolism*
-
Humans
-
Hydrophobic and Hydrophilic Interactions
-
Mice
-
Mice, Knockout
-
Models, Biological*
-
Muscle Contraction / physiology*
-
Muscle Proteins / chemistry
-
Muscle Proteins / genetics
-
Muscle Proteins / metabolism*
-
Muscle, Skeletal / chemistry
-
Muscle, Skeletal / metabolism*
-
Nuclear Magnetic Resonance, Biomolecular / methods
-
Peptides / chemistry
-
Peptides / genetics
-
Peptides / metabolism
-
Protein Structure, Tertiary / physiology
-
Ryanodine Receptor Calcium Release Channel / chemistry
-
Ryanodine Receptor Calcium Release Channel / genetics
-
Ryanodine Receptor Calcium Release Channel / metabolism*
-
S100 Proteins / chemistry
-
S100 Proteins / genetics
-
S100 Proteins / metabolism*
-
Static Electricity
Substances
-
Calmodulin
-
Muscle Proteins
-
Peptides
-
Ryanodine Receptor Calcium Release Channel
-
S100 Proteins
-
S100A1 protein
-
Calcium