Binding Partners of Slap (Research Paper Sample)

Binding Partners of Slap
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Abstract
SLAP means src like adapter protein which contains SRC HOMOLOGY 2 (SH2) and Src homology (SH3) domains that are closely related to that of cytoplasmic Src family tyrosine kinases. SLAP functions has been studied in the context of lymphocyte signaling where it functions in the Cbl dependent down regulation of a broad range of antigen receptor signaling. Slap also plays a role in regulation of membrane receptors including members of receptors tyrosine kinase family. In this review, we will investigate the role of slap in regulation of the activity of N-methyl-D-aspartate receptors (NMDARs). The review present data showing that in activation of ephrin (Eph) receptors in dissociated neuronal cultures by chimeric preclustered eph-Fc ligands may lead to recruitment of NMDA and Slap receptors (Kato and Nicole 2005). Using established heterologous systems as method of collecting data slap does not alter baseline activity of NMDA receprtos and it does not affect Src-dependent potentiation of NMDA receptors currents in Xenopus oocytes. The review also shows how slap modulates the level of NMDA receptors as it is a part of homeostatic mechanism. Therefore the project proposal is a structure into aim and justification, literature review, methodology, research timeline, and bibliography.
Aim and Justification
The slap has some binding partners which play certain roles in regulating NMDAR. Slap has a 34-kDa proteins that contain SH2 and SH3 domains and unique 104-amino acid.it also contains ephrin receptors that are largest in the family of receptor tyrosine kinases and are divide into two i.e. (EphA and EphB).based on sequence homologies and binding specify. The slap, through their modular domains, mediates the formation of multiprotein complexes. The SH2 bind phosphoproteins with phosphoryted tyrosine while SH3 domains recognize proline –rich sequences. Much is known about binding partners of slap/slap2 SH2 but binding partners for SH3 is illusive and it shows different binding specify than that of Src. Thus the research aims to elucidate how SH2 domain mediates differences in slap signaling. By identifying and understanding how these partners of slap work, we are able to understand their role and function in regulating NMDARs. The research will help us know how the partners play role in formation of synapses and how NMDARS can be recruited alongside slap in an Ephs dependent manner. The research also aims in knowing how slap offers protection from NMDAR-induced extocity and modulates NMDAR signaling (Kato and Nicolle 2005).
Introduction
Intracellular signal transduction is a process that involves assembly of multi-protein complexes in a manner that is spatially and temporally regulated. Adaptor proteins consist of protein-lipid or modular protein-protein interaction domains to facilitate formation of signaling. The Src- like adaptors i.e. SLAP and SLAP2 are the most extensively studied for their role of signaling and expressed in hematopoietic tissues. The importance of both type of slap is well established in regulating the signaling and trafficking of components of T cell receptors and B cells receptor. SLAP/SLAP2 also play important role in signaling by receptor tyrosine kinases (RTKs) (Wagey and Raymond 2001). Some growth factors mediate their signaling by binding to RTKs that induces receptor dimerization and catalytic activation. Binding sites for SH2 containing proteins such as adaptor protein and Src family kinases are created when activated receptors phosphorylate tyrosine residues within their domain. According to these signaling complexes are activated and at some appropriate times they are subsequently down regulated. This research, therefore, implicate slap as key regulators of signaling and highlights areas of future investigation.
Literature Review
Slap is expressed strongly in the forehead although its function there is still uknown.it was initially identified in a yeast two-hybrid screen using cytoplasmic tail of EphrinA2 as bait. It was argued that slap encodes a -kDa protein containing SH2 and SH3 domains and unique amino acid. It has been studied in immune systems that it inhibits T-cell receptor and is involved in the internalization and degradation of TRC subunit (Wagey and Raymond 2001). It also abrogates the mitogenic response to growth factors antagonizing the mitotic activity of Src kinase. During the development of central nervous system, ephrin receptors which constitute the largest known family of receptor tyrosine kinase, and membrane-bound ligands, have been implicated in various patterns of events. They both act as contact-dependent adhesive molecules that are implicated in development of synapses and their functioning. Based on sequence of homologies and binding capacity, ephrin are dividing into two i.e. EphA and EphB.EphBs play a role in formation of synapses, transforming dentric filopodiato spines and also clustering N-methyl-D-aspartate receptors (Martinez and Soriano 2005) .They are also plastically implicated in synaptic thus modulating NMDAR function. About EphAs less is known but some evidence suggests that they contribute in induction of synaptogenesis, maturation, spine morphology and collapse. They also alters stability of synaptic boutons hence modulating synaptic plasticity and also aids in reorganization of the cytoskeleton and regulating adhesion to the extracellular matrix. However acute administration of EphA leads to antagonist in rat hippocampal slices whereas administration of an agonist leads to LTP-like potentiation (Pasqual 1997, p.612). Therefore slap recruitments mediated but activation of Ephs at neuronal synapse. Activation of EphsA is more efficient in recruiting slaps than that of EphsB. NMDARs are also recruited alongside slaps.in this case slaps offers protection from NMDAR and also modulates its signaling.
Slap adaptor proteins use their modular domains to mediate formation of multiprotein complexes. The binding of partners starts with SH2 domains bindings with phosphoryted tyrosine residues in different context. On the other hand, SH3 domains recognize proline rich sequences.SH2 portrays same binding with specify as SFK SH2 bindings due to their homology with Src family kinases. This makes them show a strong preference for aliphatic hydrophobic residues (A,S, T)and their structure similar residues (E, D, Q, H) at pY + 1 (Wagey and Raymond 2001). The original identification of slap as a binding partner of EphA2 was shown in a phosphor manner to interact with Eph2 domain though the juxtamembrane motif. moreover the interaction of slap proteins with pTTyr motifs is facilitated by N-terminal that result in localization to the plasma membrane and association with the membrane-bound receptors explains why some amounts of nonmyristoylated slap are also localized at the plasma membrane. Therefore the association of slap with RTK molecules plays a role in RTK signaling.
Methods and Experimental Designs
The methodology, experiments and research design define the course of analysis of the research. This chapter will therefore focus on research design, search strategy, data sources, initial inclusion and exclusion criteria, quality of assessment, data extraction, synthesis and analysis and ethical concern.
Research Design
The research will seek to identify methods and materials used to study the role of slaps in regulating NMDAR. The research also will identify methods used to binding and interaction of these proteins. Therefore the research will be based on experiments, past secondary and primary sources of information handling the role of slaps in regulating NMDAR .The process of research will involve hybrid qualitative and quantitative methods of research and also exploit both primary and secondary techniques of data collection. Firsthand information will be greatly considered during the research and it will be obtained from experts with reliable knowledge on the role of slaps, how they interacting and how they help in regulating NAMDAR. Past journals that are related to the slap topic will also be used in order to reduce the relevant literature. Experiments will be the best research method while questionnaires and interviews will also be required to collect relevant information.
Data Sources and Strategy
Experiments will be done in order to get good results regarding slaps and to show how they will regulate the NMDAR.in these experiment materials suc