Cell Biology

... from active transport to vesicles

protein degradation

The majority of short-lived proteins are degraded by the ubiquitin-proteasome pathway. A protein destined for degradation is covalently attached to multiple molecules of ubiquitin, which is a highly conserved protein.

Ub-tagging for degradation is performed by a multi-enzyme cascade comprising ubiquitin-activating (E1), ubiquitin-conjugating (E2), and ubiquitin-ligating (E3) enzymes. Ubiquitinated protein is then transported to the 26S proteasome where it undergoes final degradation. The ubiquitin escort is released and recycled. Protein degradation by the Ubiquitin-proteasome pathway plays an crucial role in regulation of the cell cycle, in signal transduction, and in removal of damaged proteins.

The FHA-domain: a common motif found in nuclear kinases and: modified: "The majority of intracellular protein degradation takes place at the proteasome, a multi-subunit protease present in the cytoplasm and the nucleus of eukaryotic cells. The 20S proteasome forms a barrel-shaped structure, with the active sites of the multiple catalytic subunits facing the central cavity. [] diagram structure, diagram pathways [] This core proteasome is typically associated with a 19S cap complex, resulting in a larger assembly termed the 26S proteasome. The 19S cap complex contains several ATPase subunits, which probably act in unfolding the target proteins. In addition, the 19S complex contains at least eleven non-ATPase subunits, which are thought to function in regulation and target recognition. One of these subunits (S5a) binds to ubiquitin, which serves as a universal signal for targeting proteins to the proteasome. Two of the regulatory subunits have recently been shown to share a repeat motif with the cyclosome/APC-complex, which acts in the cell cycle dependent ubiquitination of regulatory proteins. . . We were able to identify two different homology domains, which both occur in multiple components of the regulatory proteasome as well as in several other characterised protein families"

* Determinants of half-life of proteins:
1. 'N-degron', N-end rule according to N-terminal amino acid (Ser long-lived → Asp short-lived) ,
2. amino acid sequences such as the PEST sequence, rich in proline, glutamic acid, serine, and threonine (if not masked by covalent attachment of phosphate groups to the side chains of certain amino acids)
3. exposure of degradation-signals in a partially unfolded state, allowing the signals to interact with the Ub machinery, causing the protein to become tagged by Ub. This reaction appears to be hindered by chaperone activity.

[] 26s proteasome [] 3D structure of targetted peptide [] barrel and subunits of proteasome [] proteasome assembly [] proteasome engine [] substrate swapping [] Ub-proteasome pathway [] yeast 20s proteasome ribbon, yeast 20s proteasome down the barrel, surface with bound aldehyde indicators Џ animation - proteasome Џ animation - importing, unfolding, hydrolyzing Џ

• A • adhesion • C • cell membranescellular adhesion moleculescellular signal transductioncentrioleschemotaxischloroplastcilia & flagellacommunicationconcentration gradientscytokine receptorscytoplasmcytoskeleton • E • energy transducersendoplasmic reticulumendosomesexosome • F • flagella & cilia • G • Golgi apparatusGPCRs • H • hormones • I • ion channels • L • lysosome • M • meiosismicrotubulesmitosismitochondrion • N • Nitric Oxideneurotransmissionneuronal interconnectionsnuclear membranenuclear pore • P • pinocytosisproteasomepumps • R • receptor proteinsreceptor-mediated endocytosis • S • second messengerssignaling gradientssignal transductionspindlestructure • T • transporttwo-component systems • U • ubiquitin • V • vacuolevesicle

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. . . developing since 10/06/06