Correlation between dynamics and high affinity binding in an SH2 domain interaction.
Protein-protein interfaces can consist of interactions between large numbers of residues of each molecule; some of these interactions are critical in determining binding affinity and conferring specificity, while others appear to play only a marginal role. Src-homology-2 (SH2) domains bind to proteins containing phosphorylated tyrosines, with additional specificity provided by interactions with residues C-terminal to the phosphotyrosine (pTyr) residue. While the C-terminal SH2 domain of phospholipase C-gamma 1 (PLCC SH2) interacts with eight residues of a pTyr-containing peptide from its high affinity binding site on the beta-platelet-derived growth factor receptor, it can still bind tightly to a phosphopeptide containing only three residues. Novel deuterium (2H) based nuclear magnetic resonance (NMR) spin relaxation experiments which probe the nanosecond-picosecond time scale dynamics of methyl containing side chain residues have established that certain regions of the PLCC SH2 domain contacting the residues C-terminal to the pTyr have a high degree of mobility in both the free and peptide complexed states. In contrast, there is significant restriction of motion in the pTyr binding site. These results suggest a correlation between the dynamic behavior of certain groups in the PLCC SH2 complex and their contribution to high affinity binding and binding specificity.
Kay
L E
LE
Protein Engineering Network Centres of Excellence, University of Toronto, Ontario, Canada.
Muhandiram
D R
DR
Farrow
N A
NA
Aubin
Y
Y
Forman-Kay
J D
JD
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054803:Phospholipase C delta; D011485:Protein Binding; D011487:Protein Conformation; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D010738:Type C Phospholipases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics / Q000502:physiology*
D007527:Isoenzymes; D010446:Peptide Fragments; D017479:Receptors, Platelet-Derived Growth Factor; D010738:Type C Phospholipases; D054803:Phospholipase C delta