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| Joel Sussman - | |
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Studies during the last decade have identified a family of neural cell
adhesion proteins, which are single-pass transmembrane proteins, with
substantial sequence similarity to cholinesterases (ChEs). The regions
of sequence similarity correspond to only part of their complete
sequences, thus establishing the ChE domain as a modular domain
incorporated into different proteins, i.e. cholinesterase-like
adhesion molecules (CLAMs)(1-4). CLAMs, however, devoid of catalytic
activity, since they lack residues crucial for catalysis. They appear
to play a key role in the earliest stages of the development of the
CNS and mutations, in the ChE domain of one of them, i.e. neuroligin,
has been associated with autism(5-7).
The cytoplasmic domains of CLAMs bear no sequence homology to any
known protein, and physicochemical studies show that they are
'intrinsically disordered' (8,9) when expressed in E. coli(3).
It has been estimated that a large percentage of cellular proteins
exist in this disordered state(8); e.g., in eukaryotic cells, the
estimated range is 36-63%. Using an extension of the algorithm
described by Uversky and coworkers(9), we have developed a web-based
tool, FoldIndex © (see
http://bioportal.weizmann.ac.il/fldbin/findex), which has proven
useful in predicting regions of a new protein sequence that are likely
to be disordered. We have applied FoldIndex © to examine the CLAMs
family as well as cholinesterase molecules. These 'in silico' studies
will be compared with our recent solution studies on CLAMs and
their adhesion partners.
References:
- Botti, S. A., et al., Protein Eng. 11, 415-420 (1998).
- Felder, C. E., et al., J. Molec. Graphics & Modelling 15, 318-327 (1997).
- Zeev-Ben-Mordehai, T., et al., Proteins 53, 758-767 (2003).
- Soreq, H., Seidman, S., Nature Reviews of Neuroscience 2, 294-302 (2001).
- Laumonnier, F., et al., Am. J. Hum. Genet. 74, 552-557 (2004).
- Jamain, S., et al., Nature Genet. 34, 27-29 (2003).
- Comoletti, D., et al., J. Neurosci. 24, 4889-4893 (2004).
- Dunker, A. K., et al., Biochemistry 41, 6573-6582 (2002).
- Uversky, V. N., Gillespie, J. R., Fink, A. L., Proteins 41, 415-427 (2000).
This work was supported by The Israel Ministry of Science and Technology
(MOST) infrastructure grant for the Israel Structural Proteomics Center;
by The European Commission Fifth Framework 'Quality of Life and Management
of Living Resources' 'SPINE' (Structural Proteomics in Europe) Project;
Grant number: QLG2-CT-2002-00988; and by a grant from the Divadol
Foundation (Rehovot, Israel).
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