Computational Biology - Events
Here you can view announcements of seminars and other events organised for or of interest to the community. Seminars, currently run jointly with CoMPLEX, are usually held once a term.
Previous Seminars
2011
November
TIME: Tuesday 1st November, 4pm
LOCATION: Cruciform Lecture Theatre 1
Abstract
Intrinsically
disordered proteins (IDPs) fail to form stable 3D structure on their own,
existing instead as dynamic, interconverting conformational ensembles. We have found evidence that IDPs are likely
used in many developmental pathways. Here
we will discuss our model for the canonical Wnt pathway. In this pathway, b-catenin is kept at low levels by means of
the destruction complex, which contains Axin, APC, GSK3b (a kinase), CKIa (a kinase), and b-catenin (a kinase substrate). One major
disorder-dependent role is that Axin’s long disordered segment contains
localized binding regions for GSK-3β, β-catenin, and CKIα. By assembling these
components onto one long, disordered, and flexible segment, Axin orchestrates
their interactions. A second disorder-dependent
role is that the disordered SAMP repeats of APC bind to the ordered RGS domain
of Axin. A third disorder-dependent role
in our model is that there are no specific conformational changes by which the
kinases are positioned next to their substrate; rather, everything occurs by
random, stochastic motions of the disordered connectors. The fourth disorder-dependent
role is that the disordered amino terminus of β-catenin provides all of the
sites for phosphorylation. The fifth disorder-dependent role is that the same
disordered region contains the lysines involved in β-catenin’s polyubiquitination.
The sixth disorder-dependent role is that b-catenin’s disordered tail facilitates
its entry via a narrow channel into the proteasome complex where b-catenin’s digestion
occurs. Following the binding of the Wnt signaling protein to its receptor, the
destruction complex disassembles, and b-catenin then accumulates, moves to the nucleus, and
therein turns on many genes associated with various developmental
processes. Again, disorder plays
important roles in the various steps up to and including gene regulation. In summary, disorder appears to be crucial
for development regulated by the Wnt pathway. Similarly widespread involvement of disorder
is observed for several other developmental pathways as well.
July
TIME: Friday 1st July, 3pm.
LOCATION: Medawar Lankester Lecture Theatre (This is located in the Medawar Building, behind Foster Court (map)).
Abstract
The trajectory of an evolving protein through sequence space is
constrained by the need to maintain structure and function. Residues in spatial proximity tend to co-evolve, yet attempts at inverting the
evolutionary record to derive proximity constraints have so far been
inadequate. Here we use constraints inferred from evolution to predict de novo 3D protein structures , without use of homology
modeling or fragments from known structures. Our evolutionary constraints
tackle the major obstacle in state-of-the-art de novo prediction: the ability
to sample 3D conformational space. The
predicted constraints are calculated with a method borrowed form statistical
physics using maximum entropy which solves the
inverse problem of inferring spatial proximity from patterns of co-evolution. We report prediction for 12
proteins ranging from 50-220 residues in size at a Ca-RMSD of 2.8-5.1 Å. The
predicted structures have excellent topological agreement with experimentally
determined structures, with structural elements well placed in 3D space,
suggesting they can be refined further. In this era of massive genomic
sequencing across many species, the evolutionary record captured in sequence
alignments provides an increasingly powerful source of predictive information,
in particular for protein families that have resisted experimental structure
determination.
2010
December
TIME: Wednesday 8th December, 3pm.
LOCATION: Gustave Tuck Lecture Theatre.
