Lifetime Lectures

This year, the Internation Proteolysis Society will honor two long-time contributor the field of proteolysis, Dr. Michael James and Dr. Motoharu Seiki.

Dr. Michael James

University of Alberta, Edmonton, Alberta, Canada

Dr. James is an Emeritus Distinguished University Professor in the Biochemistry Department, University of Alberta in Edmonton, Alberta, Canada.  Dr. James is one of the founding members of the longstanding, celebrated MRC (now CIHR) Group in Protein Structure and Function at the University of Alberta.  He was elected a Fellow of the Royal Society of London in 1989 and a Fellow of the Royal Society of Canada in 1985.  He earned his doctorate from Oxford University where he studied under the guidance of the late Nobel Laureate Professor Dorothy Hodgkin, O.M., F.R.S. Dr. James is a structural biologist who uses macromolecular X-ray crystallography as his primary research tool.  His major areas of research interest currently are: proteolytic enzymes and their protein inhibitors; glycolytic hydrolases and the enzymic mechanisms of carbohydrate hydrolysis; RNA dependent RNA polymerases from viruses; and the development of antiviral agents. Dr. James’ research career extends over 50 years at the University of Alberta. Collaborating with Dr. L.B. Smillie in the Biochemistry Department, Dr. Louis Delbaere in Dr. James’ group determined the structure of SGPB, a bacterial serine peptidase, the first protein structure to be determined in Canada. The first structure of an aspartic peptidase, penicillopepsin from the fungus Penicillium janthinellum, was determined in the James’ laboratory by Dr. I-Nan Hsu. This development led the way to the structure of human kidney renin determined by Dr. Anita Sielecki; renin is an enzyme important in the regulation of blood pressure. Several inhibitors of the aspartic peptidases were developed in collaboration with labs in the USA and Europe. Understanding the enzymatic mechanism of penicillopepsin was a major importance in these studies. The James’ group has established the molecular structures of several protein inhibitors of the serine proteinases. Not only have the unbound structures of these small (~6 kDa) inhibitors been solved, but also their complexes with several serine peptidases have been determined. From these several inhibitor structures a general mechanism of inhibition initially proposed by Professor Michael Laskowski Jr. has been confirmed. Included in this group of inhibitors are the third domain of the turkey ovomucoid, the potato chymotrypsin inhibitor and the related two domain inhibitor from tomatoes, eglin C from leeches, the barley seed inhibitor CI2 and the chymotrypsin/elastase inhibitor from the nematode, Ascaris.

Lecture: A Proposal for a Substrate-Assisted Catalytic Mechanism for Serine Peptidases

Michael N. G. James1, Jiang Yin1, Juan Colazo1, Fabricio Mosquera2, John C. Vederas2

Departments of 1Biochemistry and 2Chemistry, University of Alberta, Edmonton, Alberta, Canada

Perhaps the most studied of the peptidases is the chymotrypsin family. The enzymatic mechanism involving the “catalytic triad” is firmly established in people’s minds. There are parts of the acylation step, however, that remain unclear. It is well known in Physical Chemistry that OH groups are poor nucleophiles if they are nucleophilic at all. His57 has a pKa for the imidazolyl ring of ~6.5 to 7.0; the pKa of the Ser195 OH group is somewhere between 13.0 and 15.0. So how does the Ser195 OH transfer its proton to His57Nε2 in order to become nucleophilic? As far as I can tell this point has never been dealt with satisfactorily. Mike Laskowski Jr. and his coworkers have studied the interactions and inhibition kinetics of a huge number of variants of the third domain of the turkey ovomucoid bound to a panel of six serine peptidases. My lab has determined the medium-resolution (and a few high resolution) structures of many of the P1 variants of OMTKY3 bound to SGPB, Chymotrypsin and Porcine Pancreatic Elastase. From all of these studies we feel that we have an excellent view of the substrate-bound form of the serine peptidases. Close examination of these structures has led to a new hypothesis regarding the transfer of the proton on Ser195 OH to His57Nε2. Several fluorogenic substrates and substrate analogues based on this hypothesis have been synthesized and the resulting activity assays have lent strong support for the new proposal. This story forms the basis for my presentation.

Dr. Motoharu Seiki

Kanazawa University, Japan

I obtained Ph.D. in molecular biology from Kanazawa University in 1981 by the identification of the chromosomal replication origin of Bacillus subtilis (Seiki,, Nature, 1979). To start cancer research, I moved to Cancer Institute (Tokyo), and succeeded to identify the genome structure of the first human retrovirus (HTLV-1) that causes human leukemia (Adult T-cell Leukemia) (Seiki, et. al. PNAS, 1982, 1983; Nature, 1984). Then, I studied cancer metastasis by joining to the Lance Liotta's laboratory at NCI, USA for a year, became a professor of Kanazawa University (1989), and started MMP research as a new project. Discovery of the first membrane type MMP (MT1-MMP/MMP-14) was an achievement of the new project (Sato et al. Nature 1994). I continued the study in the University of Tokyo until retirement (1997-2014). Presently, I am a research professor of Kanazawa University, where I trying to develop cancer diagnostic methods.

Lecture: Playing with MT1-MMP/MMP-14 for 25 years

My study to identify MMPs that play a central role in the invasion of cancer cells started 25 years ago. As a result, MT1-MMP / MMP-14, the first membrane-type enzyme in the MMP family, was discovered (Sato et al. Nature, 1994). MT1-MMP plays a pivotal role in promoting cancer cell growth, invasion, and metastasis through proteolytic conversion of variety of proteins on the cell surface. In addition, the cytoplasmic tail of MT1-MMP activates HIF transcription factors in a non-proteolytic manner. My current view on how cancer cells are affected by the expression of MT1-MMP will be presented.

© IPS2017 / Webmaster / Crafted using Sandbox

IPS2017 General Meeting Website navigationMenu

Latest news: Registration now open!X