Short linear motif core and flanking regions modulate retinoblastoma protein binding affinity and specificity.
Palopoli, N., Gonzalez Foutel, N. S., Gibson, T. J. and Chemes, L. B.
Department of Science and Technology, Universidad Nacional de Quilmes, CONICET. Roque Saenz Pena 352. CP (B1876BXD), Bernal, Buenos Aires, Argentina.
Structural Bioinformatics Unit, Fundacion Instituto Leloir and IIBBA-CONICET. Av. Patricias Argentinas 435 CP 1405, Buenos Aires, Argentina.
Protein Structure Function and Engineering Laboratory, Fundacion Instituto Leloir and IIBBA-CONICET. Av. Patricias Argentinas435 CP 1405, Buenos Aires, Argentina.
Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117, Heidelberg, Germany.
Protein Structure Function and Engineering Laboratory, Fundacion Instituto Leloir and IIBBA-CONICET. Av. Patricias Argentinas 435 CP 1405, Buenos Aires, Argentina.
Instituto de Investigaciones Biotecnologicas IIB-INTECH, Universidad Nacional de San Martin. Av. 25 de Mayo y Francia CP 1650, San Martin, Buenos Aires, Argentina.
Departamento de Fisiologia y Biologia Molecular y Celular (DFBMC), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. Intendente Guiraldes 2160, Ciudad Universitaria, C1428EGA, Argentina.
Pocket proteins retinoblastoma (pRb), p107 and p130 are negative regulators of cellular proliferation and multifunctional proteins regulating development, differentiation and chromatin structure. The retinoblastoma protein is a potent tumor suppressor mutated in a wide range of human cancers, and oncogenic viruses often interfere with cell cycle regulation by inactivating pRb. The LxCxE and pRb AB groove short linear motifs (SLiMs) are key to many pocket protein mediated interactions including host and viral partners. A review of available experimental evidence reveals that several core residues composing each motif instance are determinants for binding. In the LxCxE motif, a fourth hydrophobic position that might allow variable spacing is required for binding. In both motifs, flanking regions including charged stretches and phosphorylation sites can fine-tune the binding affinity and specificity of pocket protein SLiM-mediated interactions. Flanking regions can modulate pocket protein binding specificity, or tune the high affinity interactions of viral proteins that hijack the pRb network. The location of SLiMs within intrinsically disordered regions allows faster evolutionary rates that enable viruses to acquire a functional variant of the core motif by convergent evolution, and subsequently test numerous combinations of flanking regions towards maximizing interaction specificity and affinity. This knowledge can guide future efforts directed at the design of peptide-based compounds that can target pocket proteins to regulate the G1/S cell cycle checkpoint or impair viral mediated pRb inactivation.
Protein Engineering Design and Selection 31(3): 69-77 (2018)