A Proteome-wide screen for mammalian SxIP motif-containing microtubule plus-end tracking proteins.
Jiang, K., Toedt, G., Montenegro Gouveia, S., Davey, N.E., Hua, S., van der Vaart, B., Grigoriev, I., Larsen, J., Pedersen, L.B., Bezstarosti, K., Lince-Faria, M., Demmers, J., Steinmetz, M.O., Gibson, T.J. & Akhmanova, A.
Curr Biol. 2012 Oct 9;22(19):1800-7. doi: 10.1016/j.cub.2012.07.047. Epub 2012Aug 9.
Microtubule plus-end tracking proteins (+TIPs) are structurally and functionally diverse factors that accumulate at the growing microtubule plus-ends, connect them to various cellular structures, and control microtubule dynamics [1, 2]. EB1 and its homologs are +TIPs that can autonomously recognize growing microtubule ends and recruit to them a variety of other proteins. Numerous +TIPs bind to end binding (EB) proteins through natively unstructured basic and serine-rich polypeptide regions containing a core SxIP motif (serine-any amino acid-isoleucine-proline) . The SxIP consensus sequence is short, and the surrounding sequences show high variability, raising the possibility that undiscovered SxIP containing +TIPs are encoded in mammalian genomes. Here, we performed a proteome-wide search for mammalian SxIP-containing +TIPs by combining biochemical and bioinformatics approaches. We have identified a set of previously uncharacterized EB partners that have the capacity to accumulate at the growing microtubule ends, including protein kinases, a small GTPase, centriole-, membrane-, and actin-associated proteins. We show that one of the newly identified +TIPs, CEP104, interacts with CP110 and CEP97 at the centriole and is required for ciliogenesis. Our study reveals the complexity of the mammalian +TIP interactome and provides a basis for investigating the molecular crosstalk between microtubule ends and other cellular structures.
Linear motifs: lost in (pre)translation.
Weatheritt, R.J. & Gibson, T.J.
Trends Biochem Sci. 2012 Aug;37(8):333-41. doi: 10.1016/j.tibs.2012.05.001. Epub2012 Jun 15.
Pretranslational modification by alternative splicing, alternative promoter usage and RNA editing enables the production of multiple protein isoforms from a single gene. A large quantity of data now supports the notion that short linear motifs (SLiMs), which are protein interaction modules enriched within intrinsically disordered regions, are key for the functional diversification of these isoforms. The inclusion or removal of these SLiMs can switch the subcellular localisation of an isoform, promote cooperative associations, refine the affinity of an interaction, coordinate phase transitions within the cell, and even create isoforms of opposing function. This article discusses the novel functionality enabled by the addition or removal of SLiM-containing exons by pretranslational modifications, such as alternative splicing and alternative promoter usage, and how these alterations enable the creation and modulation of complex regulatory and signalling pathways.
Motif switches: decision-making in cell regulation.
Van Roey, K., Gibson, T.J. & Davey, N.E.
Curr Opin Struct Biol. 2012 Jun;22(3):378-85. doi: 10.1016/j.sbi.2012.03.004.Epub 2012 Apr 3.
Tight regulation of gene products from transcription to protein degradation is required for reliable and robust control of eukaryotic cell physiology. Many of the mechanisms directing cell regulation rely on proteins detecting the state of the cell through context-dependent, tuneable interactions. These interactions underlie the ability of proteins to make decisions by combining regulatory information encoded in a protein's expression level, localisation and modification state. This raises the question, how do proteins integrate available information to correctly make decisions? Over the past decade pioneering work on the nature and function of intrinsically disordered protein regions has revealed many elegant switching mechanisms that underlie cell signalling and regulation, prompting a reevaluation of their role in cooperative decision-making.
ELM--the database of eukaryotic linear motifs.
Dinkel, H., Michael, S., Weatheritt, R.J., Davey, N.E., Van Roey, K., Altenberg, B., Toedt, G., Uyar, B., Seiler, M., Budd, A., Jodicke, L., Dammert, M.A., Schroeter, C., Hammer, M., Schmidt, T., Jehl, P., McGuigan, C., Dymecka, M., Chica, C., Luck, K., Via, A., Chatr-Aryamontri, A., Haslam, N., Grebnev, G., Edwards, R.J., Steinmetz, M.O., Meiselbach, H., Diella, F. & Gibson, T.J.
Nucleic Acids Res. 2012 Jan 1;40(D1):D242-D251. Epub 2011 Nov 21.
Linear motifs are short, evolutionarily plastic components of regulatory proteins and provide low-affinity interaction interfaces. These compact modules play central roles in mediating every aspect of the regulatory functionality of the cell. They are particularly prominent in mediating cell signaling, controlling protein turnover and directing protein localization. Given their importance, our understanding of motifs is surprisingly limited, largely as a result of the difficulty of discovery, both experimentally and computationally. The Eukaryotic Linear Motif (ELM) resource at http://elm.eu.org provides the biological community with a comprehensive database of known experimentally validated motifs, and an exploratory tool to discover putative linear motifs in user-submitted protein sequences. The current update of the ELM database comprises 1800 annotated motif instances representing 170 distinct functional classes, including approximately 500 novel instances and 24 novel classes. Several older motif class entries have been also revisited, improving annotation and adding novel instances. Furthermore, addition of full-text search capabilities, an enhanced interface and simplified batch download has improved the overall accessibility of the ELM data. The motif discovery portion of the ELM resource has added conservation, and structural attributes have been incorporated to aid users to discriminate biologically relevant motifs from stochastically occurring non-functional instances.