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      Structure determination of human Lck unique and SH3 domains by nuclear magnetic resonance spectroscopy

      research-article
      Author(s): 1 , 1 , 2 , 3 ,
      Publication date (Electronic):
      Journal: BMC Structural Biology
      Publisher: BioMed Central

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          Abstract

          Background

          Protein tyrosine kinases are involved in signal transduction pathways that regulate cell growth, differentiation, activation and transformation. Human lymphocyte specific kinase (Lck) is a 56 kDa protein involved in T-cell- and IL2-receptor signaling. Three-dimensional structures are known for SH3, SH2 and kinase domains of Lck as well as for other tyrosine kinases. No structure is known for the unique domain of any Src-type tyrosine kinase.

          Results

          Lck(1–120) comprising unique and SH3 domains was structurally investigated by nuclear magnetic resonance spectroscopy. We found the unique domain, in contrast to the SH3 part, to have basically no defined structural elements. The solution structure of the SH3 part could be determined with very high precision. It does not show significant differences to Lck SH3 in the absence of the unique domain. Minor differences were observed to the X-ray structure of Lck SH3.

          Conclusion

          The unique domain of Lck does not contain any defined structure elements in the absence of ligands and membranes. Presence of the unique domain is not relevant to the three-dimensional structure of the Lck SH3 domain.

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          Most cited references19

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          MOLMOL: a program for display and analysis of macromolecular structures.

          R Koradi, M Billeter, K Wüthrich (1996)
          MOLMOL is a molecular graphics program for display, analysis, and manipulation of three-dimensional structures of biological macromolecules, with special emphasis on nuclear magnetic resonance (NMR) solution structures of proteins and nucleic acids. MOLMOL has a graphical user interface with menus, dialog boxes, and on-line help. The display possibilities include conventional presentation, as well as novel schematic drawings, with the option of combining different presentations in one view of a molecule. Covalent molecular structures can be modified by addition or removal of individual atoms and bonds, and three-dimensional structures can be manipulated by interactive rotation about individual bonds. Special efforts were made to allow for appropriate display and analysis of the sets of typically 20-40 conformers that are conventionally used to represent the result of an NMR structure determination, using functions for superimposing sets of conformers, calculation of root mean square distance (RMSD) values, identification of hydrogen bonds, checking and displaying violations of NMR constraints, and identification and listing of short distances between pairs of hydrogen atoms.
          Article 0 comments Cited 323 times – based on 0 reviews     Review now
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            Backbone dynamics of a free and phosphopeptide-complexed Src homology 2 domain studied by 15N NMR relaxation.

            G Gish, R Muhandiram, Stuart N. Farrow … (1994)
            The backbone dynamics of the C-terminal SH2 domain of phospholipase C gamma 1 have been investigated. Two forms of the domain were studied, one in complex with a high-affinity binding peptide derived from the platelet-derived growth factor receptor and the other in the absence of this peptide. 2-D 1H-15N NMR methods, employing pulsed field gradients, were used to determine steady-state 1H-15N NOE values and T1 and T2 15N relaxation times. Backbone dynamics were characterized by the overall correlation time (tau m), order parameters (S2), effective correlation times for internal motions (tau e), and, if required, terms to account for motions on a microsecond-to-millisecond-time scale. An extended two-time-scale formalism was used for residues having relaxation data and that could not be fit adequately using a single-time-scale formalism. The overall correlation times of the uncomplexed and complexed forms of SH2 were found to be 9.2 and 6.5 ns, respectively, suggesting that the uncomplexed form is in a monomer-dimer equilibrium. This was subsequently confirmed by hydrodynamic measurements. Analysis of order parameters reveals that residues in the so-called phosphotyrosine-binding loop exhibited higher than average disorder in both forms of SH2. Although localized differences in order parameters were observed between the uncomplexed and complexed forms of SH2, overall, higher order parameters were not found in the peptide-bound form, indicating that on average, picosecond-time-scale disorder is not reduced upon binding peptide. The relaxation data of the SH2-phosphopeptide complex were fit with fewer exchange terms than the uncomplexed form. This may reflect the monomer-dimer equilibrium that exists in the uncomplexed form or may indicate that the complexed form has lower conformational flexibility on a microsecond-to-millisecond-time scale.
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              Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs.

              J. Turner, M. Brodsky, B. Irving … (1990)
              p56lck, a lymphocyte-specific member of the src family of cytoplasmic protein-tyrosine kinases, is associated noncovalently with the cell surface glycoproteins CD4 and CD8, which are expressed on functionally distinct subpopulations of T cells. Using transient coexpression of p56lck with CD4 or CD8 alpha in COS-7 cells, we show that the unique N-terminal region of p56lck binds to the membrane-proximal 10 and 28 cytoplasmic residues of CD8 alpha and CD4, respectively. Two cysteine residues in each of the critical sequences in CD4, CD8 alpha, and p56lck are required for association. Our results suggest a novel role for cysteine-mediated interactions between unrelated proteins and provide a model for the association of other src-like cytoplasmic kinases with transmembrane proteins.
              Article 0 comments Cited 47 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMC Struct Biol
                Title: BMC Structural Biology
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1472-6807
                Publication date Collection: 2003
                Publication date (Electronic): 7 May 2003
                Volume: 3
                Page: 3
                Affiliations
                [1 ]Institut für Molekulare Biotechnologie, 07745 Jena, Germany
                [2 ]IBI-2, Forschungszentrum Jülich, 52425 Jülich, Germany
                [3 ]Institut für Physikalische Biologie, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany
                Article
                Publisher ID: 1472-6807-3-3
                DOI: 10.1186/1472-6807-3-3
                PMC ID: 156628
                PubMed ID: 12734017
                SO-VID: a39e3bed-bab9-428c-a752-121ce41e9ab5
                Copyright © Copyright © 2003 Briese and Willbold; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
                History
                Date received : 16 March 2003
                Date accepted : 7 May 2003
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Molecular biology
                Data availability:
                ScienceOpen disciplines: Molecular biology

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