Joel L. Sussman

Joel Sussman

Joel L. Sussman is an Israeli crystallographer best known for his studies on acetylcholinesterase, a key protein involved in transmission of nerve signals. Born in Philadelphia, PA, he is the Morton and Gladys Pickman Professor of Structural Biology at the Weizmann Institute of Science, Rehovot, ISRAEL and the Director of the Israel Structural Proteomics Center

Scientific interests and contributions

Sussman was a pioneer of macromolecular refinement, developing CORELS and applying it to yeast tRNA^phe [1-2]. He subsequently determined the structures of ‘bulge’-containing DNA fragments as models for insertion mutations [3].

Sussman’s current research focuses on nervous system proteins, especially acetylcholinesterase (AChE), whose 3D structure was first determined in his lab. This structure revealed [4-8]: (a) AChE is a prototype of the α/β hydrolase fold [4]; (b) π-cation interactions play a key role in binding of acetylcholine (ACh) and ligands to AChE [4]; (c) Its ACh-binding site assisted in structure-based design of promising leads for novel anti-Alzheimer’s drugs; (d) discovered a highly asymmetric charge distribution [5] conserved in ‘cholinesterase-like adhesion molecules’ (CLAMs), and showed that their cytoplasmic domains are ‘intrinsically unfolded’ [6] with implications for neural development and plasticity, and led to an algorithm, Foldindex©, for predicting whether a protein sequence will fold; (f) revealed a novel anchoring device for AChE involving superhelical assembly of its subunits around a polyproline-II helix [7]; and (g) illuminated the specific chemical and structural damage to proteins produced by synchrotron radiation, e.g. cleavage of a specific disulfide bond even at cryo temperatures [8].

He has investigated the molecular basis for halophilicity [9] and halotolerance [10], shedding light on the molecular basis of how proteins function over extreme ranges of salt-concentration, with unexpected implications for kidney diseases. Recently, he determined the structures of acid-β-glucosidase [11], a protein defective in Gaucher disease, paving the way to novel therapeutic approaches, and of paraoxonase [12], a protein relevant to treatment of atherosclerosis.

References

(1) J.L Sussman & S.-H. Kim (1976) "Three-dimensional structure of a transfer RNA in two crystal forms" Science 192, 853-858 PMID 775636

(2) J.L. Sussman, S.R. Holbrook, G.M. Church & S.-H. Kim (1977) "A structure-factor least squares refinement procedure for macromolecular structures using constrained and restrained parameters" Acta Cryst. A33, 800-804 Abstract

(3) L. Joshua-Tor, D. Rabinovich, H. Hope, F. Frolow, E. Appella & J.L. Sussman (1988) "The three-dimensional structure of a DNA duplex containing looped out bases" Nature 334, 82-84 PMID 3386751

(4) J.L. Sussman, M. Harel, F. Frolow, C. Oefner, A. Goldman, L. Toker & I. Silman (1991) "Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein" Science 253, 872-879. PMID 1678899

(5) D.R. Ripoll, C.H. Faerman, P. Axelsen, I. Silman & J.L. Sussman (1993) "An electrostatic mechanism for substrate guidance down the aromatic gorge of acetylcholinesterase" Proc. Natl. Acad. Sci. USA 90, 5128-5132 PMID 8506359

(6) T. Zeev-Ben-Mordehai, E.H. Rydberg, A. Solomon, L. Toker, S. Botti, V.J. Auld, I. Silman & J.L. Sussman (2003) "The intracellular domain of the drosophila cholinesterase-like neural adhesion protein, gliotactin, is natively unfolded" Proteins 53, 758-767 PMID 14579366

(7) H. Dvir, M. Harel, S. Bon, W.-Q. Liu, M. Vidal, C. Garbay, J.L. Sussman, J. Massoulié & I. Silman (2004) "The synaptic acetylcholinesterase tetramer assembles around a polyproline-II helix" EMBO J. 23, 4394-4405 PMID 15526038

(8) Weik, M., Ravelli, R.B.G., Kryger, G., McSweeney, S., Raves, M., Harel, M., Gros, P., Silman, I., Kroon, J. & Sussman, J.L. (2000) "Specific chemical and structural damage to proteins produced by synchrotron radiation" Proc. Natl. Acad. Sci. USA 97, 623-628. PMID 10639129

(9) O. Dym, M. Mevarech & J.L. Sussman (1995) "Structural features that stabilize Halophilic malate dehydrogenase from an Archaebacterium" Science 267, 1344-1346 Abstract

(10) L. Premkumar, H.M. Greenblatt, U. Bagashwar, T. Savchenkoa, I. Gokhmana, J.L. Sussman & A. Zamir (2005) "3D structure of a halotolerant algal carbonic anhydrase predicts halotolerance of a mammalian homolog" Proc. Natl. Acad. Sci. USA 102, 7493-7498 PMID 15894606

(11) H. Dvir, M. Harel, A.H. McCarthy, L. Toker, I. Silman, A.H. Futerman & J.L. Sussman. X-ray structure of human acid-β-glucosidase, the defective enzyme in Gaucher disease (2003) EMBO Rep. 4, 704-709 PMID 15098021

(12) M. Harel, A. Aharoni, L. Gaidukov, B. Brumshtein, O. Khersonsky, S. Yagur, R. Meged, H. Dvir, R.B.G. Ravelli, A. McCarthy, L. Toker, I. Silman, J.L. Sussman & D.S. Tawfik (2004) "3D-Structure, mechanism and evolution of serum paraoxonases – a family of detoxifying and anti-atherosclerotic enzymes" Nat. Struct. Mol. Biol. 11, 412-419 PMID 15098021

Biographical information

Formal education and training

B.A. Cornell University (1965; Math & Physics)
PhD, MIT (1972; Biophysics, with Cyrus Levinthal)
Postdoctoral research, Hebrew University (1972; with Yehuda Lapidot)
Postdoctoral research, Duke University (1973; with Sung-Hou Kim)

Appointments and positions held

1976-80 Senior Scientists, Weizmann Institute of Science
1980-92 Associate Professor, Weizmann Institute of Science
1992-Now Professor, Weizmann Institute of Science
1984-85 Head, Dept of Structural Chemistry:
1988-89 Head, Kimmelman Center for Biomolecular Structure & Assembly
1994-99 Director, Protein Data Bank (PDB) at Brookhaven National Laboratory
2002-Now Incumbent of the Morton and Gladys Pickman Chair of Structural Biology

Honors and awards

2005 Samuel and Paula Elkeles Prize for Outstanding Scientist in Medicine in Israel (together with Israel Silman)
2006 TEVA Founders Award for Breakthroughs in Molecular Medicine (together with H. Soreq and I. Silman)
2005 Honorary Professor Chinese Academy of Science
1994 Elected member EMBO (European Molecular Biology Organization)