Database accession: MF7000595
Name: S100A4 with Ca
PDB ID: 2q91
Experimental method: X-ray (1.63 Å)
Assembly: Homodimer
Source organism: Homo sapiens
Primary publication of the structure:
Malashkevich VN, Varney KM, Garrett SC, Wilder PT, Knight D, Charpentier TH, Ramagopal UA, Almo SC, Weber DJ, Bresnick AR
Structure of Ca2+-bound S100A4 and its interaction with peptides derived from nonmuscle myosin-IIA.
(2008) Biochemistry 47: 5111-26
PMID: 18410126
Abstract:
S100A4, also known as mts1, is a member of the S100 family of Ca2+-binding proteins that is directly involved in tumor invasion and metastasis via interactions with specific protein targets, including nonmuscle myosin-IIA (MIIA). Human S100A4 binds two Ca2+ ions with the typical EF-hand exhibiting an affinity that is nearly 1 order of magnitude tighter than that of the pseudo-EF-hand. To examine how Ca2+ modifies the overall organization and structure of the protein, we determined the 1.7 A crystal structure of the human Ca2+-S100A4. Ca2+ binding induces a large reorientation of helix 3 in the typical EF-hand. This reorganization exposes a hydrophobic cleft that is comprised of residues from the hinge region,helix 3, and helix 4, which afford specific target recognition and binding. The Ca2+-dependent conformational change is required for S100A4 to bind peptide sequences derived from the C-terminal portion of the MIIA rod with submicromolar affinity. In addition, the level of binding of Ca2+ to both EF-hands increases by 1 order of magnitude in the presence of MIIA. NMR spectroscopy studies demonstrate that following titration with a MIIA peptide, the largest chemical shift perturbations and exchange broadening effects occur for residues in the hydrophobic pocket of Ca2+-S100A4. Most of these residues are not exposed in apo-S100A4 and explain the Ca2+ dependence of formation of theS100A4-MIIA complex. These studies provide the foundation for understanding S100A4 target recognition and may support the development of reagents that interfere with S100A4 function.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
actin binding actin binding
calcium ion binding calcium ion binding
calcium-dependent protein binding calcium-dependent protein binding
chemoattractant activity chemoattractant activity
identical protein binding identical protein binding
RAGE receptor binding RAGE receptor binding
RNA binding RNA binding
transition metal ion binding transition metal ion binding
Biological process:
epithelial to mesenchymal transition epithelial to mesenchymal transition
positive regulation of canonical NF-kappaB signal transduction positive regulation of canonical NF-kappaB signal transduction
Cellular component:
collagen-containing extracellular matrix collagen-containing extracellular matrix
cytosol cytosol
extracellular exosome extracellular exosome
extracellular region extracellular region
extracellular space extracellular space
nucleoplasm nucleoplasm
nucleus nucleus
perinuclear region of cytoplasm perinuclear region of cytoplasm
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: A, B
Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.
Number of unique protein segments: 1
Name: Protein S100-A4
Source organism: Homo sapiens
Length: 101 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMACPLEKALDVMVSTFHKYSGKEGDKFKLNKSELKELLTRELPSFLGKRTDEAAFQKLMSNLDSNRDNEVDFQEYCVFLSCIAMMCNEFFEGFPDKQPRKK
UniProtKB AC: P26447 (positions: 2-97)
Coverage: 95%
Name: Protein S100-A4
Source organism: Homo sapiens
Length: 101 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMACPLEKALDVMVSTFHKYSGKEGDKFKLNKSELKELLTRELPSFLGKRTDEAAFQKLMSNLDSNRDNEVDFQEYCVFLSCIAMMCNEFFEGFPDKQPRKK
UniProtKB AC: P26447 (positions: 2-97)
Coverage: 95%
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Representative domain in related structures: S-100/ICaBP type EF hand dimer
Evidence level: Direct evidence
Evidence coverage: The full structure participates in mutual synergistic folding.
Complex Evidence:
GuHCl-induced denaturation of the S100B protein dimer showed that it follows a two-state unfolding/refolding process (PMID:11888280). Other S100 proteins also showed two-state unfolding, no folded monomers were observed (PMID:18346834, PMID:18706914). The dimer has a globular and compact structure with the four helices in each subunit aligning to form a unicornate-type four-helix bundle (PMID:11790100). The hydrophobic core extends through the dimer interface.
Chain A:
N/A
Chain B:
N/A
Surface and contacts features:
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). Download the CIF file (.cif)
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