Brief Biography

• BSc, Polytechnic Institute of Brooklyn (1962)
• PhD, Massachusetts Institute of Technology (1967)
• Post-doctoral fellow, Harvard Medical School (1968-70)

Mailing Address 

Molecular Structure & Function
Research Institute
Hill Wing, Room 3427A
The Hospital for Sick Children
555 University Avenue
Toronto, On. M5G 1X8 Canada

Research Interests

Membrane proteins - either in low or non-supply, or with critical mutations - underlie the causes of many human diseases, including several forms of cancer, diabetes, multiple sclerosis, cystic fibrosis, and muscular dystrophy. However, while the structures of literally thousands of water-soluble proteins have been solved by X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, only a handful of membrane proteins have been solved to high resolution. Yet, one cannot deduce the molecular mechanisms of a disease or move directly toward drug design/therapy, without a structure. Our central hypothesis is that key relationships between biological function and membrane protein structure can be defined through characterization of the transmembrane (TM) segments which comprise the membrane domains of proteins of proteins by several criteria, including composition, sequence, chain length, hydrophobicity, conformation, and elucidation of specific TM-TM interactions within membranes. We have been approaching a fundamental understanding of the structures of membrane-based domains of proteins through three inter-related peptide- and protein-based routes.

De novo design of membrane-spanning peptides – Our goals are to design, synthesize, and evaluate the properties of series' of 'host-guest' hydrophobic peptides as mimics of transmembrane segments in proteins. One such Ala-based series has prototypical sequence KKAAAXAAAAAXAAWAAXAAAKKKK-amide (where X = each of the 20 commonly-occurring amino acids). Structural studies on these peptides in membrane environments by CD and fluorescence have identified the existence of a 'threshold hydrophobicity' requirement which, when met, allows spontaneous peptide insertion into membranes; we are also able to quantify this threshold value precisely, and examine the extent to which natural TM segments conform to it. Our lab has also determined the relative helical propensity of the 20 amino acids when proteins are placed in non-polar environments. Analysis of TM and non-TM helix databases suggests that such environment-dependent helical propensities are used to advantage in vivo for sorting and distributing helices between globular and membrane proteins. Peptide hydrophobicity and helicity in membranes are being analyzed in combination as a predictive method for identification of protein TM segments. A program called TM/Finder, developed by our lab for this purpose, is available free on the Internet and can be found at the following link.

http://tmfinder.research.sickkids.ca/cgi-bin/TMFinderForm.cgi.

Hydrophobic peptides designed as mimics of transmembrane segments transfer spontaneously from water into lipid micelles - and take fully helical structures - when their average hydrophobicity is above an experimentally-determined threshold (approximately that of a poly-alanine segment). Peptides of prototypic sequence KKAAAXAAAAAXAAWAAXAAAKKKK-amide, where X = hydrophobic residues, exhibit this behaviour. Several peptides of this basic design have now been demonstrated to display antibiotic activity against E.coli and a number of gram positive and gram negative bacteria.

Mutagenesis and dimerization motifs of viral coat proteins - The major coat protein (gene VIII) from bacteriophage M13 (a virus-like particle) is a 50-residue protein that inserts as a single-spanning membrane protein into the host E. coli membrane where it disrupts the lipid packing, and allows phage DNA to penetrate. We have developed a convenient method of site-directed mutagenesis of the coat protein; a library of over 100 M13 coat protein single- and double-site mutants has been produced in our laboratory. The goals of this research are to achieve correlation of viability with residue type (hydrophobicity, location, volume) to (i) obtain a detailed picture of the sequence/composition requirements for insertion of a protein into a membrane; and (ii) to discover the dimerization motifs through which the strands interact with one another to elicit the membrane-based helix-helix interactions typically required for function.

Mutagenesis experiments on viral coat proteins have shown that key transmembrane segment mutations (such as Val-to-Ala) stabilize tight symmetric helical dimers when they occur within protein-protein interfaces (V31A; right). The same mutation at a lipid-facing position (V29A; center) produces weaker, asymmetric dimers that are relatively similar to wild type structures (left).

Structure of the chloride channel domain of the cystic fibrosis transmembrane conductance regulator (CFTR) – CFTR is a 1,480-residue protein which is the gene product associated with CF disease. CFTR is a complex membrane protein with 12 putative TM strands in two domains of six each. Our laboratory is involved in cloning and expression (in E. coli) to produce milligram quantities of multi-strand segments of the CFTR channel domains - focusing on two-TM strand ‘helical hairpins’ as a minimal model of tertiary contacts between helices in membranes. We project that these will be suitable for high-resolution structural characterization, ultimately by high-resolution NMR spectroscopy in lipid micelle environments. Concurrently, molecular modeling is performed to predict the residues participating in inter-helical motifs. Our goals are to produce and study normal and CF-phenotypic mutants to gain insights into the

Critical mutations in the membrane-spanning domains of proteins cause many human diseases, including cystic fibrosis. We expressed (in E. coli) helix-loop-helix segments of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel domain. Structural analysis demonstrated that a neutral-to-charged CF-phenotypic point mutation (valine-232 to aspartic acid) in the CFTR transmembrane (TM) helix 4 induces a hydrogen bond with neighboring wild type glutamine-207 in TM helix 3. The diagram depicts an energy-minimized model of antiparallel CFTR TM helical segments 3 and 4; (a) is the space-filling model with interacting Asp and Gln sites depicted in black (carbon atoms) and red (oxygen atoms), and (b) is a ball-and-stick detail showing the hydrogen bonding interactions between Asp-232 and Gln-207. As an electrostatic crosslink within a hydrocarbon (membrane) phase, such a hydrogen bond could alter the normal assembly and alignment of CFTR TM helices, and/or impede their movement in response to substrate transport. Our results imply that membrane proteins like CFTR may be vulnerable to loss of function through formation of membrane-buried interhelical hydrogen bonds by partnering of neighboring polar side chains.

Publications

Yin LM, Edwards MA, Li J, Yip CM, Deber CM:  Roles of hydrophobicity and charge distribution of cationic antimicrobial peptides in peptide-membrane interactions.  J. Biol. Chem. E-pub 17 Jan. 2012.

Tulumello DV, Deber CM:  Efficiency of detergents at maintaining membrane protein structures in their biologically relevant forms.  Biochim. Biophys. Acta - Biomembranes E-pub 21 Jan. 2012.

Rath A, Deber CM:  Protein structure in membrane domains. Ann. Rev. of Biophysics 41,115-135 (2012).

Mulvihill CM, Deber CM:  Structural basis for misfolding at a disease phenotypic position in CFTR:  Comparison of TM3/4 helix-loop helix constructs with TM4 peptides.  Biochim. Biophys. Acta - Biomembranes 1818, 49-54 (2012).

Ng DP, Poulsen BE, Deber CM:  Membrane protein misassembly in disease. Biochim. Biophys. Acta – Biomembranes E-pub 5 August 2011.

Tulumello DV, Deber CM:  Membrane protein folding in detergents. In Modern Methods in Protein Chemistry, de Gruyter Publishers, Berlin, Germany (2011).

Poulsen BE, Cunningham F, Lee KY, Deber CM:  Modulation of substrate efflux in bacterial small multidrug resistance proteins by mutations at the dimer interface. J. Bacteriology 193, 5929-5935 (2011).

Tulumello DV, Deber CM:  Positions of polar amino acids alter interactions between transmembrane segments and detergents. Biochemistry 50, 3928-3935 (2011).

Cunningham F, Poulsen BE, Ip W, Deber CM: Beta-branched residues adjacent to GG4 motifs promote the efficient association of glycophorin A transmembrane helices. Peptide Science 96, 340-347 (2011).

Norholm MHH, Cunningham F, Deber CM, von Heijne G:  Converting a marginally hydrophobic globular protein into a membrane protein.  J. Molecular Biology 407, 171-179 (2011).

Rath A, Nadeau VG, Poulsen BE, Ng DP, Deber CM:  Novel hydrophobic standards for membrane protein molecular weight determinations via sodium dodecyl sulfate – polyacrylamide gel electrophoresis. Biochemistry 49, 10589-10591 (2010).

Mulvihill CM, Deber CM:  Evidence that the translocon may function as a hydropathy partitioning filter. Biochim Biophys Acta – Biomembranes 1798, 1995-1998 (2010).

Ng DP, Deber CM:  Modulation of the oligomerization of myelin proteolipid protein (PLP) by transmembrane helix interaction motifs.  Biochemistry 49, 6896-6902 (2010).

Deber CM, Brodsky B, Rath A:  Proline residues in proteins.  In Encyclopedia of Life Sciences, John Wiley & Sons Ltd., Chichester, U.K. (2010).

Ng DP, Deber CM:  Deletion of a terminal residue disrupts oligomerization of a transmembrane alpha-helix.  Biochem. Cell Biol. 88, 339-345 (2010).

Tulumello DV, Deber CM:  SDS micelles as a membrane-mimetic environment for transmembrane segments. Biochemistry 48, 12096-12103 (2009).

Grant CV, Yang Y, Glibowicka M, Wu CH, Park SH, Deber CM, Opella SJ:  A modified Alderman-Grant coil makes possible an efficient cross-coil probe for high field solid-state NMR of lossy biological samples. J. Mag. Resonance 201, 87-92 (2009).

Kim Chiaw P, Gonska T, Huan L-J, Gagnon S, Ly D, Sweezey N, Rotin D, Deber CM, Bear CE:  Functional rescue of deltaF508CFTR by peptides designed to mimic sorting motifs. Chemistry & Biology 16, 520-530 (2009).

Cunningham F, Rath A,  Deber CM:  Hydrophobic peptide segments in soluble proteins competent for membrane insertion:  role in amyloidogenesis.  Adv. Exp. Med. Biol. 611, 299-300 (2009).

Cheung JC, Kim Chiaw P, Deber CM, Bear CE:  A novel method for cytosolic delivery of peptide cargo.  J. Controlled Release 137, 2-7 (2009).

Rath A, Tulumello DV, Deber CM: Peptide models of membrane protein folding. (‘Current Topics’ Review) Biochemistry 48, 3036-3045 (2009).

Poulsen BE, Rath A, Deber CM: The assembly motif of a bacterial small multidrug resistance protein. J. Biol. Chem. 284, 9870-9875 (2009).

Rath A, Glibowicka M, Nadeau VG, Chen G, Deber CM: Detergent binding explains anomalous SDS-PAGE migration of membrane proteins. Proc. Natl. Acad. Sci. USA 106, 1760-1765 (2009).

Cunningham F, Rath A, Johnson RM, Deber CM: Distinctions between hydrophobic helices in soluble proteins and transmembrane segments as factors in protein sorting. J. Biol. Chem. 284, 5395-5402 (2009).

Glukhov E, Burrows LL, Deber CM: Membrane interactions of designed cationic antimicrobial peptides: the two thresholds. Biopolymers 89, 360-371 (2008).

Cheung JC, Deber CM: Misfolding of the cystic fibrosis transmembrane conductance regulator and disease. ('Current Topics' Review) Biochemistry 47, 1465-1473 (2008).

Deber CM, Cheung JC, Rath A: Defining the defect in F508del CFTR: a soluble problem? ('Commentary') Chemistry & Biology 15, 3-4 (2008).

Rath A, Deber CM: Surface recognition elements of membrane protein oligomerization. Proteins. Struct. Funct. Bioinform. 70, 786-793 (2008).

Wehbi H, Gasmi-Seabrook G, Choi MY, Deber CM: Positional dependence of non-native polar mutations on folding of CFTR helical hairpins. Biochim. Biophys. Acta (Biomembranes) 1778, 79-87 (2008).

Glukhov E, Burrows LL, Deber CM: Membrane interactions of designed cationic antimicrobial peptides: the two thresholds. Biopolymers 89, 360-371 (2008).

Johnson RM, Hecht K, Deber CM: Aromatic and cation-pi interactions enhance helix helix association in a membrane environment. Biochemistry 46, 9208 - 9214 (2007).

Glukhov E, Shulga Y, Epand RF, Dicu A, Topham MK, Deber CM, Epand RM: Membrane interactions of the hydrophobic segment of diacylglycerol kinase epsilon. Biochim. Biophys. Acta 1768, 2549-2558 (2007).

Plotkowski ML, Kim S, Phillips ML, Partridge AW, Deber CM, Bowie JU: The transmembrane domain of myelin protein zero can form dimers: possible implications for myelin construction. Biochemistry 46, 12164-12173 (2007).

Kuo HH, Chan C, Burrows LL, Deber CM: Hydrophobic interactions in complexes of antimicrobial peptides with bacterial polysaccharides. Chem Biol Drug Des. 69, 405-412 (2007).

Wehbi H, Rath A, Glibowicka M, Deber CM: Role of the extracellular loop in the folding of a CFTR transmembrane helical hairpin. Biochemistry 46, 7099-7106 (2007).

Cunningham F, Deber CM: Optimizing synthesis and expression of transmembrane peptides and proteins. Methods 41, 370-380 (2007).

Rath A, Deber CM: Membrane protein assembly patterns reflect selection for non-proliferative structures. FEBS Lett. 581, 335-41 (2007).

Rath A, Johnson RM, Deber CM: Peptides as transmembrane segments: decrypting the determinants for helix-helix interactions in membrane proteins. Biopolymers (Peptide Science) 88. 217-232 (2007).

Johnson RM, Rath A, Deber CM: The position of the Gly-xxx-Gly motrif in transmembrane segments modulates dimer affinity. Biochem. Cell Biol. 84, 1006-1012 (2006).

Wellhauser L, Kuo HH, Stratford F, Ramjeesingh M, Huan LJ, Luong W, Deber CM, Bear CE: Nucleotides bind to the carboxy terminus of ClC-5. Biochem. J. 398(2), 289-294 (2006).

Johnson RM, Rath A, Melnyk RA, Deber CM: Lipid solvation effects contribute to the affinity of Gly-xxx-Gly motif-mediated helix-helix interactions. Biochemistry 45, 8507-8515 (2006).

Go MY, Kim S, Partridge AW, Melnyk RA, Rath A, Bowie JU, Deber CM, Mogridge J: Self-association of the transmembrane domain of an anthrax toxin receptor. J. Mol. Biol. 360, 145-156 (2006).

Burrows LL, Stark M, Chan C, Glukhov E, Sinnadurai S, Deber CM: Activity of novel non-amphipathic cationic antimicrobial peptides against pathogenic Candida species. J. Antimicrobial Chemotherapy 57, 899-907 (2006).

Rath A, Melnyk RA, Deber CM: Evidence for assembly of small multidrug resistance proteins by a "two-faced" transmembrane helix. J. Biol. Chem. 281, 15546-15553 (2006).

Glukhov E, Stark M, Burrows LL, Deber CM.: Basis for selectivity of cationic antimicrobial peptides for bacterial vs. mammalian membranes. J. Biol. Chem. 280, 33960-33967 (2005).

Choi MY, Partridge AW, Daniels C, Du K, Lukacs GL, Deber CM.: Destabilization of the transmembrane domain induces misfolding in a phenotypic mutant of CFTR. J. Biol. Chem. 280, 4968-4974 (2005).

Rath A, Davidson AR, Deber CM.: The structure of ‘unstructured’ regions in peptides and proteins: role of the polyproline II helix in protein folding and recognition. Peptide Science 80, 179-185 (2005).

Johnson RM, Heslop CL, Deber CM.: Hydrophobic helical hairpins: Design and packing interactions in membrane environments. Biochemistry 43, 14361–14369 (2004).

Chan C, Burrows LL, Deber CM.: Helix induction in antimicrobial peptides by alginate in biofilms. J. Biol. Chem. 279, 38749-38754 (2004).

Choi MY, Cardarelli L, Therien AG, Deber CM.: Non-native interhelical hydrogen bonds in the CFTR transmembrane domain modulated by polar mutations. Biochemistry 43, 8077-8083 (2004).

Melnyk RA, Kim S, Curran AR, Engelman DM, Bowie JU, Deber CM. The affinity of GXXXG motifs in transmembrane helix-helix interactions is modulated through long-range communication. J. Biol. Chem. 279, 16591-16597 (2004).

Partridge AW, Therien AG, Deber CM. Missense mutations in transmembrane domains of proteins: phenotypic propensity for human disease. Proteins: Structure, Function and Bioinformatics 54, 648-656 (2004).

Tang Y-C, Deber CM. Aqueous solubility and membrane interactions of hydrophobic peptides with peptoid tags. Peptide Science 76, 110-118 (2004).

A detailed list of Dr. Deber's publications can be found on Pub Med. »»

Intellectual Property

• Novel Peptide Antibiotics

For information on this and other business opportunities, visit the Corporate Ventures website.