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Intrinsically disordered proteins
Laboratory of Intrinsically Disordered Proteins
Group Leader: Dr. Peter Tompa
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Address:
Institute of Enzymology of the
Hungarian Academy of Sciences
Karolina út 29
H-1113, Budapest Hungary

P. O. Box 7
H-1518 Budapest Hungary

E-mail: tompa (at) enzim.hu
Phone: +36-1-279-3143
Fax: +36-1-466-5465

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The classical structure-function paradigm states that a well-defined 3D structure is the prerequisite of protein function, as witnessed by more than 50000 structures deposited in the Protein Data Bank (PDB). These structures solved at atomic resolution provide the basis of our understanding of how enzymes, receptors, transporters and structural proteins function. An array of recent structural studies, however, cautions that this view portrays too simple a picture, because many proteins or regions of proteins are intrinsically disordered (IDPs/IDRs). The structure of IDPs resembles the denatured states of ordered proteins, best described as an ensemble of rapidly interconverting alternative conformations, which, nevertheless, is their native, functional state. Structural disorder has been an evolutionary success-story, reaching high proportions in the proteomes of higher eukaryotes. In the human proteome, for example, about 12% of the proteins are fully disordered and about 50% of the proteins contain at least one long (>30 consecutive residues) disordered region. Currently, there is experimental evidence for the structural disorder of about 1200 disordered regions in 520 proteins, collected and deposited in the DisProt database (www.disprot.org). tp_site_1.jpg
Disordered FG-domains regulate gating by the nuclear pore complex (NPC). From Patel et al. (2007) Cell 129: 83-96

 tp_site_2.gif This high proportion results from the functional advantages structural disorder confers on proteins, which either manifests itself in functional modes enabled directly by the disordered state (entropic chain functions) or in molecular recognition, such as specificity without excessive binding strength, fast interaction, large binding surface or adaptability in binding. In accord, IDPs/IDRs fulfill essential cell-biological functions, most apparent in signal transduction and transcription regulation. Due to the key regulatory functions of IDPs, they are also often causally linked with debilitating diseases, such as cancer (e.g. p53, BRCA1) and neurodegenerative disorders (e.g. prion protein, α-synuclein). The existence and effective functioning of IDPs defy the classical structure-function paradigm and demand it to be re-assessed and extended.
Functional classification of IDPs (IUPs). From Tompa (2005) FEBS Lett.15: 3346-54



This re-assessment and extension requires the synergy of studies at a variety of levels, including proteomics, bioinformatics and detailed structure-function studies of individual proteins. The laboratory pioneered several approaches in IDP research and is actively pursuing studies. Our major areas of research are: i) bioinformatic analysis of structural disorder; ii) detailed characterization of the chaperone function of IDPs, with particular focus on disordered plant stress proteins; iii) proteomics and databases; iv) characterization and potential inhibition of the amyloid formation of α-synuclein ; v) detailed characterization of IDPs securin and calpastatin ; vi) extension of the structure-function paradigm be developing novel concepts for the description of the unique functional modes of IDPs. Many of the results and concepts are discussed in the first monograph of the area “Structure and function of intrinsically disordered proteins” by Peter Tompa, to be published in September 2009 by Taylor and Francis.