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Plenary Speakers

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Christopher M. Overall
Code / Date
PL-1 / March 29 (Thu) 09:10-09:50
Speaker
Christopher M. Overall   CV
Affiliation
University of British Columbia, Canada
Title
Target Identification by TAILS N-Terminal Positional Proteomics Leads to Development of a Pharmacological Molecular Corrector for Impaired NF-kB Activation
Career
Professor Overall started his UBC lab in 1993 after a MRC Centennial Fellowship with Dr. Michael Smith, Nobel Laureate (1989-), with subsequent pharmaceutical experience at British Biotech, Oxford (1997-1998) and Novartis, Basel (2004/2008). He is a Tier 1 Canada Research Chair in Protease Proteomics, Life Sciences Institute with cross-appointments/affiliations with the Center for Blood Research, Department Biochemistry/Molecular Biology, and is an Honorary Professor, Albert-Ludwigs Universität Freiburg.
As recognized by the 2017 HUPO Discovery Award in Proteomics Sciences, he is best known for two related but distinct scientific achievements. The first is development of new proteomic methods for discovery of protein substrates of proteolytic enzymes e.g., TAILS, PICS, ATOMS, which allow identification of protease cleavage sites and substrates in vivo for the first time. Thereby he established the field of degradomics. The second is levering these techniques to reveal new and often unexpected biological roles for proteases in vivo and their aberrations in disease. The significance of his research has been recognized by many Awards including: 2002 CIHR Researcher of the Year; Tony Pawson Award (2014); and the Proteomass Scientific Society Award (2017). He was elected to the HUPO Executive Council and to Co-Chair HUPO’s Chromosome-Centric Human Proteome Project.
With 258 refereed papers (h-index 85,~26,000 citations, 30 >200), including 27 Nature(1), Science(2), and daughter journal (24) papers, he has mentored 37 PDFs—4 of whom are Full Professors, 3 Associate Professors, and 8 are Assistant Professors.
Abstract

Genetically encoded, protein termini isoforms are generated during translation, following which, we find termini are highly dynamic, being frequently trimmed or generated by a large array of exo- and endopeptidases. Hence, global approaches for the identification of protein terminal peptides provides key information on the stability and function of most proteins and hence, the functional state of the proteome. Proteomics methods will be presented that enrich and annotate terminomes—Terminal Amino Isotopic Labelling of Substrates (TAILS, Kleifeld et al Nature Biotech 28, 281-288) and C-TAILS for the C-terminome (Schilling et al Nature Methods 2010). Our DB TopFIND (http://clipserve.clip.ubc.ca/topfind) integrates information on N and C-termini, protease cleavage sites and N-terminal modifications and reveals surprisingly widespread modification and truncation of N and C-termini in 4 model species.
These techniques will be illustrated by our discovery of metalloprotease domains in bacterial flagella of at least 74 bacterial species. To identify “flagellinolysin”-cleavage sites we employed PICS (Proteome-wide Identification of Protease Cleavage Specificity), a proteomic technique that employs proteome-derived peptide libraries as proteolytic substrate screens. After incubation with either recombinant flagellin hypervariable region (flagellinolysin), or with intact flagella, the neo amino-termini were biotinylated, affinity isolated, and identified by LC-MS/MS. Flagellinolysin and flagella cleaved nearly 1,000 different peptides. With ~20,000 flagellin copies per ~10-μm flagella this assembles the largest proteolytic complex known revealing this family as enzymatic biopolymers with potential for numerous roles in saprophytic bacteria and in pathogens.
Uncontrolled and upregulated proteases are attractive drug targets in a variety of malignancies, inflammatory and autoimmune diseases. However, increasing protease activity to correct delayed or insufficient protease expression or activity in disease is chemically and therapeutically challenging. MALT1 is central for transducing lymphocyte antigen receptor activation of NF-κB. By TAILS we have identified new MALT1 substrates in the NF-κB pathway. We recently discovered nanomolar, selective allosteric inhibitors of MALT1 paracaspase activity that bind by replacing the side chain of Trp580 and locking the protease in an inactive conformation. Interestingly, we identified a patient homozygous for a hypomorphic MALT1 mutation at Trp580Ser who suffered from combined immunodeficiency. The new allosteric inhibitors stabilized the mutant protein and increased the Tm to that of wild-type MALT1. In so doing the small molecule pharmacologic molecular corrector restored MALT1 protein levels in MALT1mut/mut lymphocytes, rescuing canonical NF-κB and JNK signaling, and improving the proteolytic activity of MALT1-Trp580Ser to restore substrate cleavage. Thus, a low molecular weight pharmacological corrector compound rescued protease deficiency by substituting for the mutated residue to restore function and increase cleavage activity, inspiring potential precision therapies to increase mutant enzyme activity.

 

Bernhard Küster
Code / Date
PL-2 / March 29 (Thu) 16:25-17:05
Speaker
Bernhard Küster   CV
Affiliation
Technical University of Munich, Germany
Title
The target landscape of clinical kinase drugs
Career
Professor Kuster has been engaging researches in the field of chemical and functional proteomics. He firstly developed Kino-bead for kinome analysis and reported TPP (Thermal proteome profiling) for target identification of non-tagging small molecules. His group has uncovered how proteins interact with each other and with active pharmaceutical agents, and how these can be used for individual approaches to clinical treatment.
Abstract

Kinase inhibitors have developed into important cancer drugs because de-regulated protein kinases are often driving the disease. Close to 40 such molecules have been approved for use in humans and several hundred are undergoing clinical trials. As most compounds target the ATP binding pocket, drug selectivity among the 500 human kinases is a recurring question. Clinicallyspeaking, polypharmacology can be beneficial as well as detrimental. Therefore, knowing the full target spectrum of a drug is important but rarely available. We have used a quantitative chemical proteomics approach to profile 240 clinical kinase inhibitors in a dose dependent fashion in cancer cell lysates to identify thousands of drug-protein interactions. This presentation will outline how this information is generated and how it can be used to identify molecular targets of toxicity, re-purposing existing drugs for new indications, finding combinations of drugs to overcome resistance or provide starting points for new drug discovery.

 

David R. Goodlett
Code / Date
PL-3 / March 30 (Fri) 09:10-09:50
Speaker
David R. Goodlett   CV
Affiliation
University of Maryland School of Pharmacy, USA
Title
From a Histroical Review of Developments leading to Shotgun Proteomics to Longitudinal Profiling
Career
Prof Goodlett has spent his career using mass spectrometry to solve biomedical problems via novel technology and software developments. He has been active in a variety of fields including medicine, oceanography, pharmacy, microbiology, proteomics (including clinical applications), lipidomics, and protein & glycolipid structure-function relationships publishing over 240 papers. He has been a Professor at the University of Maryland (2013-present) and the University of Washington (2004-2012) as well as first Director of Proteomics at the Institute for Systems Biology (2000-2003). From 2012-2016 he was a Finland Distinguished Professor; https://www.youtube.com/watch?v=jfOOMNJivvY. He is an Editor at Rapid Communications in Mass Spectrometry and a co-organizer of www.msbm.org. In 2018 he will join the International Centre for Cancer Vaccine Science (ICCVS) at the University of Gdansk as a Visiting Professor to set up proteomics within the centre.
Abstract

This lecture will begin with a review the technical developments leading to what we now refer to as shotgun proteomics using label-free quantitation. In the heart of the lecture we will review our work at the University of Turku (2012-2016) on the Finnish Type 1 Diabetes (T1D) Prediction and Prevention (DIPP) study. This project began in 1994, the year the term Proteome was coined, with collection of follow-up samples from children with increased genetic risk for T1D. We recently reported our work (Moulder et al. Diabetes 2015) comparing serum proteomes during the early stages of life in children who progressed to develop T1D to identify potential changes that could be associated with disease onset or activity and detected before the appearance of T1D associated autoantibodies. Proteomic profiles were compared between those who remained healthy, but were at genetic risk of developing T1D, to those who developed T1D, matched by age, gender, sample periodicity and risk group. Proteomic profiles were generated by a combination of iTRAQ and label free analyses on 26 subjects from approximately six time points per patient representing periods from early infancy, to seroconversion and diagnosis in their teenage years. Functional annotation enrichment analysis highlighted proteins related to lipid transport and inflammatory response. On the basis of top scoring pair analysis, classification of the T1D developing subjects was observed with a success rate of 91% indicating that we have identified new candidates whose levels change in children during the early development of T1D. Related work will be reviewed that in total constitutes a systems biology approach to analysis of these children. We will conclude with thoughts on the importance of longitudinal sampling for biomarker discovery versus pair-wise comparisons that have largely failed to deliver.

 

Young-Ki Paik
Code / Date
PL-4 / March 30 (Fri) 16:05-16:45
Speaker
Young-Ki Paik   CV
Affiliation
Yonsei University, Korea
Title
Quest for Dark Proteins in Biomedical Sciences
Career
After receiving his doctorate degree at the University of Missouri-Columbia, USA, in 1983, Prof. Paik took a postdoctoral position at the Gladstone Institute of Cardiovascular Diseases, UCSF until 1986 when he became a Staff Research Investigator. After leaving the Gladstone Institute in 1989, he returned to Seoul and had an associate professorship at the Department of Biochemistry, Hanyang University (1989-1993) and the Department of Biochemistry, Yonsei University (1993-95). In 1995, Paik became a full Professor, and in 2000 was appointed Director of the Yonsei Proteome Research Center (www.proteomix.org), a flagship proteome center in Asia where he has carried out research on the biochemistry of aging and pheromone metabolism in C. elegans and cancer proteomics. He has been appointed as Underwood Distinguished Professor (2009-2018) is currently Distinguished Research Professor Emeritus and Director of Yonsei Proteome Research Center, Yonsei University, Seoul. He is one of the co-founders of AOHUPO and KHUPO and former President of KHUPO (2001-2005), AOHUPO (2008-2010), HUPO (2009-10) and KSBMB (2012). He was also one of the key co-founders of international consortium of ‘Chromosome-centric Human Proteome Project’ and serves currently Chair of this global project (www.c-hpp.org). Paik has authored or co-authored over 190 peer-reviewed scientific journal publications including Nature, Nature Biotechnology and Hepatology. His lab discovered daumone, a nematode pheromone which induces dauer state under stressful growth conditions. He received numerous prestigious scientific awards including Kyung-Am Award, A Scientist of Month Award (Ministry of Science and Technology and Ministry of Health and Welfare), DI Awards, MSD Awards and HUPO Distinguished Service Award. He was Director of Natural Science Division of the Korean Academy of Science and Technology and currently serves Co-Chair of Center of Science Diplomacy, the Korean Federation of Science and Technology Societies.
Abstract

The Chromosome-centric Human Proteome Project (C-HPP) consortium (1) recently adopted the concept of a dark proteome, a collective of structurally or functionally less characterized proteins. This category includes missing proteins (2,575 proteins), protein evidence 1 proteins with unknown functions (uPE1, 1,232 proteins) and proteoforms translated by single nucleotide polymorphisms, alternatively spliced variants, small open reading frames and long non-coding RNAs. To this end, the C-HPP has launched the neXt-CP50 initiative along with its ongoing neXt-MP50 campaign to expedite the characterization and definitions of a certain number of dark proteins (2). In this talk, I will first address the historical aspect and progress made by the C-HPP (2012-2017) and discuss various strategies regarding the discovery of dark proteins. Second, in addition to the dark proteome, I will explore the methods used to identify the novel functions of some regulatory proteins involved in cancers, reproductive diseases or neuronal networks in terms of their potential utilities in biomedical applications. We anticipate that the complexity of human biology and disease will be better understood as the list of functionally validated proteins increases, and this will be achieved by clarifying the dark proteome in a coordinated manner at the global level.

References
1: Paik YK et al., The Chromosome-Centric Human Proteome Project for cataloging proteins encoded in the genome. Nat Biotechnol. 2012;30(3):221-3.
2: Paik YK, Omenn GS, Hancock WS, Lane L, Overall CM, Advances in the Chromosome-Centric Human Proteome Project: Looking to the future. Expert Rev Proteomics. 2017;14:1059-71.

 

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