Autoinhibitory interaction in the multidomain adaptor protein Nck: possible roles in improving specificity and functional diversity.
Nck is a functionally versatile multidomain adaptor protein consisting of one SH2 and three SH3 domains. In most cases, the SH2 domain mediates binding to tyrosine-phosphorylated receptors or cytosolic proteins, which leads to the formation of larger protein complexes via the SH3 domains. Nck plays a pivotal role in T-cell receptor-mediated reorganization of the actin cytoskeleton as well as in the formation of the immunological synapses. The modular domain structure and the functionality of the individual domains suggest that they might act independently. Here we report an interesting intramolecular interaction within Nck that occurs between a noncanonical yet conserved (K/R)x(K/R)RxxS sequence in the linker between the first and second SH3 domain (SH3.1/SH3.2) and the second SH3 domain (SH3.2). Because this interaction masks the proline-rich sequence binding site of the SH3.2 domain, the intramolecular interaction is self-inhibitory. This intramolecular interaction could, at least partially, explain the remarkable specificity of Nck toward proteins with proline-rich sequences. It may prevent nonspecific low-affinity binding while keeping the site available for high-affinity bivalent ligands that can bind multiple sites in Nck. This indicates that Nck does not simply adopt a "beads on a string" architecture but incorporates a higher-order organization for improved specificity and functionality.
Takeuchi
Koh
K
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
Sun
Zhen-Yu J
ZY
Park
Sunghyouk
S
Wagner
Gerhard
G
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains / Q000235:genetics*
D002352:Carrier Proteins; D008024:Ligands; D011506:Proteins