Protein structure Synapt

There is now a growing interest in proteomic studies of brain synapses. Recent studies have revealed a high molecular complexity in the pre- and postsynaptic areas, with thousands of proteins [6]. An important investigation for the future is to identify posttranslational modifications, miscoded as well as misfolded proteins, likely to have an impact on different aspects of synaptic function as a response to the environment as well as to the lifestyle. The first challenge is to identify and quantify the presence and variation of different proteins in key structures of the pre- and postsynaptic areas in order to relate protein structures to synaptic function. Recently, a new model has been presented describing the molecular complexity of the synapse with important aspects in emotions, thinking, memory, and consciousness [7] (Fig. 17.2). 

In addition to the proteins discussed above, neuronal SNAREs were reported to interact with numerous other proteins in a specific manner, but in most cases both the structural basis and the biological function of these interactions need to be defined. For instance, synaptophysin, a membrane protein of synaptic vesicles, forms a complex with synaptobrevin in which synaptobrevin is not available for interactions with its partner SNAREs syntaxin 1A and SNAP-25, suggesting that this complex represents a reserve pool of recruitable synaptobrevin (Becher et al. 1999) or regulates interactions between the vesicle-associated synaptobrevin and the plasmalem-mal SNAREs. Alternatively, it has been suggested that this complex is involved in synaptobrevin sorting to synaptic vesicles. 

The toxin is a 150-kDa zinc-dependent metalloproteinase that cleaves proteins involved in the docking and fusion of synaptic vesicles to the membrane at the neuromuscular junction. The toxin consists of two chains a heavy chain (100 kDa) and a light chain (50kDa) linked by a disulfide bond. The crystal structure of the molecule has been solved to 3.3-A resolution [49]. The protein structure revealed a 50-residue belt that partially obscures the active site access channel the authors note that this unusual feature makes rational inhibitor design more difficult. 

Nakagawa, T., Putai, K., Lashuel, H. A., Lo, I., Okamoto, K., Walz, T., Hayashi, Y., and Sheng, M. (2004). Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions. Neuron 44, 453—467. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

This selectively neurotoxic compound damages the sympathetic nerve endings. Because of its structural similarity to dopamine, it is actively taken up into the synaptic system. Once taken up, it oxidizes to a reactive quinone, which may bind to protein and produce reactive free radicals and superoxide. These events destroy the nerve terminals and nerve cells also in some cases. 

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