Disordered Motifs and Domains in Cell Control
Poster Session I
24-POS
Board 24
Binding Properties of Linear Motif-mediated Viral Retinoblastoma-target Protein
Interactions
Lucía B. Chemes
1
, Nicolás González Foutel
1
, Gonzalo de Prat Gay
1
1
Leloir Institute-IIBBA CONICET Av. Patricias Argentinas
Many proteins from pathogenic viruses have intrinsically disordered (IDP) domains harboring
short linear motifs that target cellular functions. The LxCxE and E2F motifs mediate high-
affinity binding to the retinoblastoma (Rb) tumor suppressor, promoting cell cycle progress and
efficient replication of the viral genome. However, persistent expression of viral proteins can
lead to cell transformation and cancer. Interference with host functions is key to understanding
viral pathogenesis. However, current insight into structure-function relationships of viral proteins
is still scarce. A review of experimentally reported instances revealed LxCxE and E2F motifs
presence in viral and cellular partners. However, viral instances are located exclusively within
IDP regions and enriched in sequence features enhancing binding affinity, suggesting they may
have evolved to allow for effective competition with cellular interactions. Cellular instances are
located in exposed loops or helices, suggesting a stronger entropic cost for binding. Solution
binding studies of the LxCxE and E2F motifs from four cellular and viral Rb targets showed that
the E2F2 transcription factor motif bound Rb with high affinity (
K
D
= 12 nM). Opposed to the
two-state behavior of the HPV E7 LxCxE site, binding involves slow conformational
rearrangements of the E2F2 motif. The individual LxCxE and E2F motifs from the adenovirus
E1A protein presented
K
D
values in the 200 nM range, suggesting that the full-length protein has
sub-nanomolar affinity and that both E1A and HPV E7 compete effectively for binding with the
low affinity (
K
D
= 10 µM) histone deacetylase protein. These results suggest that intrinsic
disorder may favor the evolution of both conformational and sequence features within viral
linear motifs, endowing viral proteins with high affinity interactions that interfere effectively
with host functions, and stress the need for a combined structure-function and evolutionary
analysis of pathogenic virus-host interactions.
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