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.
TIME: Tuesday 1st November, 4pm
LOCATION: Cruciform Lecture Theatre 1
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.
TIME: Friday 1st July, 3pm.
LOCATION: Medawar Lankester Lecture Theatre (This is located in the Medawar Building, behind Foster Court (map)).
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.
TIME: Wednesday 8th December, 3pm.
LOCATION: Gustave Tuck Lecture Theatre.