The guanylate kinase domain of the MAGUK PSD-95 binds dynamically to a conserved motif in MAP1a.
The postsynaptic density protein PSD-95 and related membrane-associated guanylate kinases are scaffolding proteins, whose modular interaction motifs organize protein complexes at cell junctions. The signature guanylate kinase domain (GK) contains elements of the protein's GMP-binding site but does not bind nucleotide. Instead, the GK domain has evolved from an enzyme to a protein-protein interaction motif. Here, we show that this canonical GMP-binding region interacts with microtubule-associated protein-1a (MAP1a) and we present a structural model. We determine the consensus GK-binding sequence in MAP1a and demonstrate that PSD-95 can use a similar interaction mode to bind diverse protein partners. Furthermore, we show that PSD-95 GK has adopted the conformational flexibility of the ancestral enzyme to bind its varied ligands, which suggests a mechanism of regulation.
Reese
Michael L
ML
Graduate Group in Biophysics, University of California, San Francisco, California 94143, USA.
Dakoji
Srikanth
S
Bredt
David S
DS
Dötsch
Volker
V
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D000076122:Disks Large Homolog 4 Protein; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics; D051528:Guanylate Kinases / Q000737:chemistry*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D018909:src Homology Domains
D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; C490546:Map1a protein, rat; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D051528:Guanylate Kinases