Disordered Motifs and Domains in Cell Control
Sunday Speaker Abstracts
Intrinsic Disorder, Posttranslational Modification, and Signaling Complexity
Peter E. Wright
.
The Scripps Research Institute, La Jolla, CA, USA.
Intrinsically disordered proteins (IDPs) mediate critical regulatory functions in the cell, including
regulation of transcription, translation, the cell cycle, and numerous signal transduction events.
The lack of stable globular structure confers numerous functional advantages, including,
paradoxically, both binding promiscuity and high specificity in target interactions. IDPs play a
central role in dynamic regulatory networks, where their propensity for posttranslational
modifications, their rapid binding and dissociation kinetics, and their ability to interact with
multiple target proteins makes them well adapted for precise transduction of cellular signals. The
role of IDPs in dynamic cellular signaling will be illustrated by reference to pathways regulated
by the general transcriptional coactivators CBP and p300, the tumor suppressor p53, and
oncoproteins from adenovirus and human papillomavirus. CBP and p300 are central nodes in
eukaryotic transcriptional regulatory networks and transcription factors must compete for
binding to the limiting concentrations of CBP/p300 present in the cell. Many intrinsically
disordered proteins contain multipartite interaction motifs that perform an essential function in
the integration of complex signaling networks. The role of multipartite binding motifs and
posttranslational modifications in regulation of signaling pathways will be discussed.
Acidic Patches in Nucleophosmin Recruit Nucleolar Proteins via Arginine-Rich Linear
Motifs
Diana Mitrea
1
, Richard W. Kriwacki
1,2
.
1
St. Jude Children's Research Hospital, Memphis, TN, USA,
2
University of Tennessee Health
Science Center, Memphis, TN, USA.
The multifunctional protein Nucleophosmin (NPM1) localizes primarily to the nucleolus, where
it is involved in ribosome biogenesis, tumor suppression and nucleolar stress response. NPM1
functions as a nucleolar chaperone for several proteins and is part of the ribonucleoprotein
complexes. Utilizing a combination of bioinformatics, biophysical and structural approaches, we
identified short linear motifs enriched in arginine in a large number of the known NPM1
nucleolar interactors (Mitrea et. al PNAS (2014), 111:4466) and show that these short linear
motifs interact with highly conserved acidic patches on NPM1. Interestingly, tumor suppressor
protein ARF which suppresses NPM1-dependent ribosome biogenesis competes for the same
binding regions on NPM1 utilized for interactions with ribosomal proteins. Rigorous
understanding of the molecular mechanism utilized by NPM1 to switch between nucleolar
partners will provide critical insight into the regulation of nucleolar functions and structure.
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