Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor.
Intrinsically disordered proteins play critical but often poorly understood roles in mediating protein interactions. The interactions of disordered proteins studied to date typically entail structural stabilization, whether as a global disorder-to-order transition or minimal ordering of short linear motifs. The disordered cyclin-dependent kinase (CDK) inhibitor Sic1 interacts with a single site on its receptor Cdc4 only upon phosphorylation of its multiple dispersed CDK sites. The molecular basis for this multisite-dependent interaction with a single receptor site is not known. By NMR analysis, we show that multiple phosphorylated sites on Sic1 interact with Cdc4 in dynamic equilibrium with only local ordering around each site. Regardless of phosphorylation status, Sic1 exists in an intrinsically disordered state but is surprisingly compact with transient structure. The observation of this unusual binding mode between Sic1 and Cdc4 extends the understanding of protein interactions from predominantly static complexes to include dynamic ensembles of intrinsically disordered states.
Mittag
Tanja
T
Program in Molecular Structure and Function, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8.
Orlicky
Stephen
S
Choy
Wing-Yiu
WY
Tang
Xiaojing
X
Lin
Hong
H
Sicheri
Frank
F
Kay
Lewis E
LE
Tyers
Mike
M
Forman-Kay
Julie D
JD
D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D044783:F-Box Proteins / Q000737:chemistry / Q000378:metabolism*; D007536:Isomerism; D008024:Ligands; D010766:Phosphorylation; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*
C080443:CDC4 protein, S cerevisiae; D018797:Cell Cycle Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D044783:F-Box Proteins; D008024:Ligands; C086926:SIC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D044767:Ubiquitin-Protein Ligases