A closed binding pocket and global destabilization modify the binding properties of an alternatively spliced form of the second PDZ domain of PTP-BL.
PTP-BL is a large phosphatase that is implicated in cellular processes as diverse as cytokinesis, actin-cytoskeletal rearrangement, and apoptosis. Five PDZ domains mediate its cellular role by binding to the C termini of target proteins, forming multiprotein complexes. The second PDZ domain (PDZ2) binds to the C termini of the tumor suppressor protein APC and the LIM domain-containing protein RIL; however, in one splice variant, PDZ2as, a 5 residue insertion abrogates this binding. The insert causes distinct structural and dynamical changes in the alternatively spliced PDZ2: enlarging the L1 loop between beta2 and beta3, both lengthening and changing the orientation of the alpha2 helix, giving the base of the binding pocket less flexibility to accommodate ligands, and destabilizing the entire domain. These changes render the binding pocket incapable of binding C termini, possibly having implications in the functional role of PTP-BL.
Walma
Tine
T
Department of Biophysical Chemistry, NSRIM Center, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands.
Aelen
Jan
J
Nabuurs
Sander B
SB
Oostendorp
Marlies
M
van den Berk
Lieke
L
Hendriks
Wiljan
W
Vuister
Geerten W
GW
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism*; D060588:LIM Domain Proteins; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008840:Microfilament Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D019154:Protein Splicing / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
D025601:Adenomatous Polyposis Coli Protein; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; C486248:Pdlim4 protein, mouse; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases; C516743:Ptpn13 protein, mouse