View source for Uba1

<Structure load='UBA1.pdb' size='350' scene='69/695713/Uba1_main/1'>
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== Function ==
'''Uba1''' is an E1 protein involved in the ubiquitination pathway found in ''Saccharomyces cerevisia'', baker’s yeast. <ref name=lee> Lee I, Schindelin H. Structural Insights into E1-Catalyzed ubiquitin Activation and Transfer to Conjugating Enzymes. Cell 134, 268–278 (2008). DOI:10.1016/j.cell.2008.05.046 </ref> <ref name=gross> Groettrup, M.; Pelzer, C.; Schmidtke, G.; Hofmann, K. Activating the ubiquitin family: UBA6 challenges the field. Trends Biochem. Sci. 2008, 33, 230-237. DOI:http://dx.doi.org/10.1016/j.tibs.2008.01.005</ref> <ref name=Chen> Chen, Z. J.; Sun, L. J. Nonproteolytic Functions of ubiquitin in Cell Signaling. Mol. Cell 2009, 33, 275-286. DOI:http://dx.doi.org/10.1016/j.molcel.2009.01.014.</ref> <ref name=mc> McGrath, J. P.; Jentsch, S.; Varshavsky, A. UBA 1: an essential yeast gene encoding ubiquitin-activating enzyme. EMBO J. 1991, 10, 227-236.
</ref> Ubiquitination, a post-translational modification that conjugates ubiquitin to a target protein, has been shown to have important cellular effects, such as the marking of a protein for degradation. <ref name=lee> </ref> Ubiquitination is carried out in a three step enzymatic cascade <ref name=gross> </ref> that utilizes E1, E2, and E3 enzymes. The ubiquitin cascade starts when the E1 enzyme adenylates ubiquitin at its carboxyl terminal glycine, then ubiquitin is linked to a cysteine in the E1 enzyme resulting in an E1~Ub thioester bond. <ref name=gross> </ref>  <ref name=Chen> </ref> <ref name=mc> </ref> This ATP consuming step is followed by a ubiquitin transfer to an E2 enzyme, producing an AMP and a pyrophosphate. An E3 enzyme, along with an E2 enzyme, then catalyzes the ubiquitination of the target protein.<ref name=lee> </ref> <ref name=mc> </ref>

== Ubiquitin Interactions == 
The <scene name='69/695713/Uba1/1'>monomeric structure</scene> of Uba1 consists of six structural domains (IAD, AAD, FCCH, SCCH, 4HB, and UFD), four of which(AAD, FCCH, SCCH, and UFD) pack together to create a central cavity.  The cavity is divided into two distinct clefts (left and right) by the SCCH/AAD linker fragment. It has been suggested that Uba1 can exist as a <scene name='69/695713/Uba1/6'>dimer</scene> in solution, with two monomers non-covalently bound. Ubiquitin binds to the cysteine located on the right cleft of Uba1 which allows for ubiquitin to orient itself relative to the active site located on the left cleft. The structure of <scene name='69/695713/Uba1_monomeric_ub/2'>ubiquitin bound to Uba1</scene> (Uba1 in grey Ub in green) results in a change in conformation that buries a significant portion of Uba1 exposed surface area.  The <scene name='69/695713/Uba1_monomeric_ub_catcys_hi/1'>catalytic cysteine</scene> (Cys600) located on the SCCH domain of Uba1 forms a thioester with the C-terminus of ubiquitin. It is suggested that a significant conformation change occurs when ubiquitin binds to Uba1 due to the large distance (~35 Å) between the catalytic cysteine residue and the adenylation active site. 

Aside from the catalytic site interactions there are two main interactions between ubiquitin and Uba1, a hydrophobic interface, and the polar interface between ubiquitin and first-catalytic cysteine half domain, FCCH, which contains the E1 active site cysteine. The <scene name='69/695713/Uba1_monomeric_ub_hydro/3'>hydrophobic interactions</scene> are maximized by interactions between the Phe898, Leu903, and Phe905 on Uba1(seen in magenta) and the Leu8, Ile44 and Val70(seen in red) residues on ubiquitin1. This interaction is further stabilized by a <scene name='69/695713/Uba1_monomeric_ub_8/1'>hydrogen bond</scene> between the Asn900 residue on Uba1 and the carbonyl oxygen of ubiquitin’s Leu81. The interaction between ubiquitin’s c-terminus and the FCCH domain of Uba1 relies on a deep groove formed from residues 175-265 in Uba1. Four polar residues on ubiquitin, Lys11, Thr12, Gln31, and Asp32, form hydrogen bonds with three polar residues, Arg202, Gly204, and Glu206, on Uba1 <ref name=lee> </ref> 

==E2 Interactions==
When ubiquitin binds, Uba1 then coordinates the transfer of ubiquitin onto an E2 enzyme. The E2 enzyme (seen in salmon) <scene name='69/695713/Uba1_ubc4/1'>interacts</scene> with Uba1 in the catalytic cavity composed of the AAD, FCCH, SCCH, and the UFD domains. A transthioesterfication of ubiquitin occurs between the catalytic cysteine of Uba1 to the catalytic cysteine of the E2 enzyme. The E2 enzyme, in conjunction with the E3 enzyme, transfers the ubiquitin onto its final substrate.<ref name=lee> </ref> <ref name=walden>Walden H, Podgorski MS, Huang DT, Miller DW, Howard RJ, Minor DL Jr, Holton JM, Schulman BA. The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an E1. Molecular Cell 12, 1427–1437 (2003). DOI:10.1016/S1097-2765(03)00452-0 </ref>

==3D structure of Uba1==

[[Ubiquitin activating enzyme]]

==References ==

<references/>
--[[User:Dalton R. Gibbs|Dalton R. Gibbs]] 05:14, 25 February 2015 (IST)--[[User:Taylor Light|Taylor Light]] 05:14, 25 February 2015 (IST)-- Bruce Liberi 25 February 2015