Section: Research

William Royer, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Biochemistry and Molecular Pharmacology

Structural basis for assembly and functional regulation in macromolecular complexes

The focus of research in this laboratory is the investigation of the structural principles governing the assembly of protein molecules. We primarily use x-ray crystallography to obtain three-dimensional protein structures and complement this structural information with site-directed mutagenesis and biophysical techniques. Assembly of polypeptide chains can endow them with additional important functional properties. Classic among these are allosteric interactions in which the binding of small ligands act to regulate protein function. We are investigating this process using a number of invertebrate oxygen carrier molecules as models to understand the structural basis for intersubunit communication.   Transmission of signals within cells often involves protein assembly.  We are investigating such signaling in the interferon regulatory factors (IRFs) whose phosphorylation-induced assembly triggers activation of a number of target genes involved in host defense mechanisms.

Invertebrate oxygen carriers

These systems range from the simplest possible allosteric system, exemplified by a dimeric hemoglobin which we have shown to have a completely novel mechanism for cooperativity, to much more complex protein assemblages (up to several million Daltons ). The use of these systems will help to elucidate structural principles for allosteric regulation as well as provide information crucial for the design of blood substitutes.  The dimeric hemoglobin from the blood clam, Scapharca inaequivalvis, is a particularly good model system for investigating allostery.  The simplicity of this system has allowed us to elucidate the central role for ordered water molecules in the communication between subunits.  In collaboration with Dr. Francesca Massi (BMP), we are using NMR to investigate the role of interface dynamics in the communication between subunits, for which the ligand-linked reorganization of interface water molecules may play a key role.  In collaboration with Dr. Vukica Šrajer (University of Chicago ), we are using time-resolved crystallography to follow the allosteric transitions as they occur at sub nanosecond time resolution.  One intriguing finding from this work is that movement of interface water molecules may facilitate the early nanosecond events in the transition between alternate states.       

Interferon regulatory factors (IRFs)

IRF family members play important roles in innate immunity, inflammation and apoptosis. Activation of these proteins in the cytoplasm is triggered by phosphorylation of Ser/Thr residues in a C-terminal autoinhibitory region. Phosphylation stimulates dimerization, translocation into the nucleus and assembly with the coactivator CBP/p300 to activate transcription of type I interferons and other target genes.  In collaboration with Dr. Celia Schiffer (BMP) and Dr. Kate Fitzgerald (Medicine), we are continuing work on the structural basis for activation of IRFs that was pioneered by our extraordinary colleague, Dr. Kai Lin, before his tragic death from cancer.  Our crystal structure of dimeric pseudophosphorylated IRF-5, in comparison with structures of monomeric IRF-3 determined by Dr. Lin, has revealed the structural basis for IRF activation.  Phosphorylation triggers a striking conformational rearrangement of the C-terminal region converting it from an autoinhibitory to a dimerization role.  Activated dimers are then translocated into the nucleus, where they assemble with transcriptional coactivators to activate transcription.  Understanding IRF regulation, particularly that of IRF-5, is of potential clinical importance, as therapeutic agents that enhance activity could combat viral infection or tumor growth, whereas agents that attenuate activity could be used to minimize harmful inflammatory responses.

Office: NRB 921, Lab 970 H&I
Phone: 508-856-6912
E-mail: William.Royer@umassmed.edu
Keywords: Biophysics, Structural Biology, Biochemistry

More on William Royer's Research Research | Figures | Publications | Rotations | Personnel | Biography View All Sections on One Page