Our lab is broadly interested in understanding the chemical/molecular basis of biological processes and trying to use the molecular understanding of these biological processes to benefit human well-being. Specifically, we are interested in studying several interesting enzyme-catalyzed protein posttranslational modifications (Figure 1). We combine organic synthesis, biochemistry, biophysics, molecular biology, and cell biology to study the enzymology of the biosynthetic enzymes, identify the modified proteins, and study how the modification affects protein structure/function and thus the biological significance of the modification.
The human genome encodes ~30,000 genes, a number that is much lower than originally estimated, given that a much simpler organism Caenorhabditis elegans has a genome of ~20,000. However, protein diversification by posttranslational modification could expand the number of functionally unique protein variants to more than 10 times the genome size. In a sense, it is the diverse protein posttranslational modifications, plus transcriptional control, alternative RNA splicing, and miRNA, that enable a limited number of genes to carry out numerous functions with precise temporal and spatial control. Therefore, in the "post-genomic era", studying protein posttranslational modifications in detail should help to understand protein functions both at the individual protein and functional proteomic levels. With the exception of a few, such as phosphorylation and ubiquitination (recognized by the 2004 Nobel Prize in Chemistry), many posttranslational modifications have not been well studied, as they require more sophisticated synthetic and analytical chemistry tools. Thus, protein posttranslational modifications provide unique opportunities for chemists interested in understanding biology.
Figure 1. Diversification of proteins by posttranslational modifications can expand the number of functionally unique protein variants to more than 10 times of the genome size. Studying posttranslational modifications is thus essential to understand protein functions at both individual protein and proteomic levels. Shown here are a few examples of protein posttranslational modifications that are being studied in our lab. |
H.
Lin, W.M. Abida, R.T. Sauer, V.W. Cornish, “Dexamethasone-Methotrexate:
An Efficient Chemical Inducer of Protein Dimerization In
Vivo”, J. Am. Chem. Soc. 122, 4247 (2000). Featured
in Chem. & Eng. News, 78, 18, 52 (2000).
H.
Lin, V.W. Cornish, “In Vivo Protein-Protein
Interaction Assays: Beyond Proteins”, Angew. Chem.
Int. Ed. 40, 871 (2001).
H.
Lin, V.W. Cornish, “Screening
and Selection Methods for Large-Scale Analysis of Protein Function”,
Angew. Chem. Int. Ed.
41, 4402 (2002).
W.M.
Abida, B.T. Carter, E.A. Althoff. H. Lin, V.W. Cornish,
“Receptor-Dependence of the Transcription Read-Out in a Small-Molecule
Three-Hybrid System”, Chembiochem. 3,
887 (2002).
K.
Baker, C. Bleczinski, H. Lin, G. Salazar-Jimenez, D. Sengupta,
S. Krane, and V.W. Cornish, “Chemical
complementation: A reaction-independent genetic assay for enzyme
catalysis”, Proc. Natl. Acad. Sci. USA, 99,
16537 (2002). Featured in a commentary in Proc. Natl. Acad.
Sci. USA, 99, 16513-16515 (2002) and in Chem. &
Eng. News, 81, 1, 24 (2003).
A. C. Forster, Z. Tan, M. N.
L. Nalam, H. Lin, H.Qu, V. W. Cornish and S. C. Blacklow, “Programming peptidomimetic syntheses
by translating genetic codes designed de
novo”, Proc.
Natl. Acad. Sci. USA, 100, 6353 (2003). Featured in Chem. Biol., 10, 586-587
(2003) and in Chem. & Eng. News, 82, 3, 64-68
(2004).
D.
Sengupta, H. Lin, S. Goldberg, J. Mahal, V.W. Cornish,
"Correlation between catalytic efficiency and the transcription
read-out in chemical complementation, a high-throughput assay
for enzyme catalysis", Biochemistry, 43, 3570 (2004).
H.
Lin, H. Tao, V.W. Cornish, "Directed Evolution of a Glycosynthase
Via Chemical Complementation", J. Am.
Chem. Soc., 126, 15051 (2004). Featured in Chem.
& Eng. News, 82: 46, 32 (2004).
B.
T. Carter, H. Lin, S. Goldberg, J. Raushel, V.W. Cornish,
Chembiochem. 6, 2055 (2005).
H.
Lin, C.T. Walsh, "A Chemoenzymatic Approach to Novel
Glycopeptide Antibiotics", J. Am. Chem. Soc., 126,
13998 (2004).
H. Lin
(co-first author), D. Thayer, C.-H. Wong, C.T. Walsh,
"Macrolactamization of Glycosylated Peptide Thioesters
by the Thioesterase Domain of Tyrocidine Synthetase", Chem.
Biol. 11, 1635 (2004). Featured in Chem. Biol.
11, 1599, and Chem. & Eng. News, 82:
51, 47 (2004).
E.
Yeh, H. Lin, S.L. Clugston, R.M. Kohli, C.T. Walsh, "Enhanced macrocyclizing activity
of the thioesterase from tyrocidine synthetase in presence of
nonionic detergent", Chem. Biol. 11,
1573 (2004).
M. A. Fischbach, H. Lin (co-first author),
D.R. Liu, C.T. Walsh, “In vitro characterization of IroB,
a pathogen-associated C-glycosyltransferase”, Proc. Natl.
Acad. Sci. USA, 102, 571 (2005). Featured in
Proc. Natl. Acad. Sci. USA, 102, 517 (2004).
H.
Lin, M.A. Fischbach, D.R. Liu,
C.T. Walsh, “In vitro characterization of salmochelin and
enterobactin trilactone hydrolases IroD, IroE, and Fes”,
J. Am. Chem. Soc., 127, 11075 (2005).
M. Luo, H. Lin, M.A.
Fischbach, D.R. Liu, C.T. Walsh, J.T. Groves, “Enzymatic
tailoring of enterobactin alters membrane partitioning and iron
acquisition”, ACS Chem. Biol., 1, 29 (2006).
M. A. Fischbach, H. Lin, D.R. Liu, C.T. Walsh,
“How pathogenic bacteria evade mammalian sabotage in the
battle for iron”, Nat. Chem. Biol., 2, 132
(2006).
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