Professor and Director (also with Internal
Medicine); Ph.D., Yeshiva (Einstein), 1971. Molecular genetics
and evolution of the electron transport chain; cytochrome c
oxidase; mitochondria and mitochondrial diseases.
Research Interests
My
lab studies the molecular genetics and evolution of
mitochondrial genes. The genes of the electron transport chain
proteins are encoded partly by mitochondrial DNA and partly by
nuclear DNA. We have largely focused on the nuclear-encoded
subunits, particularly those of cytochrome c
oxidase (COX), the terminal enzyme complex of the respiratory
chain. The known functions of COX are carried out by the three
subunits specified by mitochondrial DNA; the role of the
nuclear subunits is only beginning to emerge and includes
regulation.
In
our focus on the function, regulation, and molecular evolution
of the nuclear subunits, we have needed to first establish the
players. To that end, we recently discovered three new
isoforms of COX, a lung and trachea-specific isoform of
subunit IV, a testes-specific isoform of subunit VIb, and a
third isoform of subunit VIII. We are currently examining the
lung-specific isoform in particular detail, both by studying
its transcriptional regulation, especially by hypoxia, to
understand its signalling circuitry and interaction with other
cellular components, and by examining a recently created mouse
null mutant.
Another
approach to function we are using is molecular evolution; we
have developed the picture that cytochrome c and subunits of complex III and COX that interact with it have
undergone a period of accelerated evolution suggestive of
positive selection at similar times in an ancestor of modern
primates. We believe that this remodeling of the electron
transport chain supported the expansion of the
energy-consuming enlarged neocortex that was taking place in
these primate lineages. We are now seeking to characterize
biochemically any modifications in electron transport that
resulted. Finally, we are interested in the relation between
rapidly evolving genes and human disease.
Selected Publications
T.R.
Schmidt, M. Goodman and L.I.
Grossman (2002). Amino acid replacement is rapid in
primates for the mature polypeptides of COX subunits, but not
for their targeting presequences. Gene
286, 13-19.
M. Yu, S.A. Jaradat and L.I. Grossman (2002). Genomic organization and promoter regulation
of human cytochrome c oxidase
subunit viia
heart/muscle isoform (COX7AH).
Biochim. Biophys. Acta 1574,
345-353.
Wildman D.E., Grossman
L.I., and Goodman M. (2002). Human and chimpanzee
functional DNA shows they are more similar to each other than
either is to other apes.
In M. Goodman and A.S. Moffat, Eds. Probing
Human Origins. Cambridge: American Academy of Arts &
Sciences Press, pp. 1-10.
D.E. Wildman, W. Wu, M. Goodman and
L.I. Grossman (2002).
Episodic positive selection in ape cytochrome c
oxidase subunit iv.
Mol. Biol. Evol. 19,
1812-1815.
J.W. Doan, T.R. Schmidt, D.E. Wildman, M. Uddin, A. Goldberg, M. Httemann, M.
Goodman, M.L. Weiss and L.I.
Grossman (2004). Coevolution of a multiprotein complex:
cytochrome c oxidase subunits show accelerated rates of nonsynonymous
substitution in anthropoid primates. Mol.
Phylogenet Evol. 33, 944-950.
L.I. Grossman, D.E. Wildman, T.R. Schmidt and M. Goodman (2004). Accelerated evolution of the electron transport chain in anthropoid primates. Trends Genet. 20 , 579-585.
J.W. Doan, T.R. Schmidt, D.E. Wildman, M Goodman, M.L. Weiss and L.I. Grossman (2005). Rapid nonsynonymous evolution of the iron sulfur protein in anthropoid primates. J. Bioenerg. Biomembr., in press.
I. Lee, A.R. Salomon, S. Ficarro, I. Mathes, F. Lottspeich, L.I. Grossman, and M. Hüttemann (2005). cAMP-dependent tyrosine phosphorylation of subunit I inhibits cytochrome c oxidase activity. J. Biol. Chem., in press.
Search Pubmed:
Lab members (Fall 2003), from left: Larry Grossman, Monica Uddin, Ick Soo Lee, Maik Httemann, Tim Schmidt, Derek Wildman, Jeff Doan
Grossman Lab |
