Sunday, July 20, 2014

Creation Moment 7/21/2014 - Tad bit "Complex"

 ...for I am fearfully and wonderfully made:
Psalm 139:14
"Ubiquitination is a crucial cellular signalling process, and is controlled on multiple levels.
Cullin–RING E3 ubiquitin ligases (CRLs) are regulated by the eight-subunit COP9 signalosome (CSN).

CSN inactivates CRLs by removing their covalently attached activator, NEDD8.

NEDD8 cleavage by CSN is catalysed by CSN5, a Zn2+-dependent isopeptidase that is inactive in isolation. Here we present the crystal structure of the entire ~350-kDa human CSN holoenzyme at 3.8 Å resolution, detailing the molecular architecture of the complex.


CSN has two organizational centres:
1) a horseshoe-shaped ring created by its six proteasome lid–CSN–initiation factor 3 (PCI) domain proteins,
2) and a large bundle formed by the carboxy-terminal α-helices of every subunit. CSN5 and its dimerization partner, CSN6, are intricately embedded at the core of the helical bundle.
In the substrate-free holoenzyme, CSN5 is autoinhibited (see below for how that works), which precludes access to the active site.

We find that neddylated CRL binding to CSN is sensed by CSN4, and communicated to CSN5 with the assistance of CSN6, resulting in activation of the deneddylase." Nature
Clearly there is DESIGN here & DESIGN = DESIGNER
P.S. - What is Autoinhibition?
"Autoinhibition plays a significant role in the regulation of many proteins. By analyzing autoinhibited proteins, we demonstrate that these proteins are enriched in intrinsic disorder because of the properties of their inhibitory modules (IMs). A comparison of autoinhibited proteins with structured and intrinsically disordered IMs revealed that in the latter group (1) multiple phosphorylation sites are highly abundant; (2) splice variants occur in greater number than in their structured cousins; and (3) activation is often associated with changes in secondary structure in the IM. Analyses of families of autoinhibited proteins revealed that the levels of disorder in IMs can vary significantly throughout homologous proteins, whereas residues located at the interfaces between the IMs and inhibited domains are conserved.
Our findings suggest that intrinsically disordered IMs provide advantages over structured ones that are likely to be exploited in the fine-tuning of the equilibrium between active and inactive states of autoinhibited proteins." Cell