The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
APC/C_Apc2-docking motif
Functional site description:
The Anaphase Promoting Complex or Cyclosome (APC/C) E3 ubiquitin ligase controls progression through the cell cycle by ubiquitylation of cell cycle regulators, which are subsequently degraded by the proteasome. The catalytic activity and substrate specificity of the APC/C depends on its association with the co-activator proteins such as Cdc20 and Cdh1, which recognize short destruction motifs present in APC/C substrates (including LIG_APCC_Dbox_1 and LIG_APCC_KENbox_2 degrons). By binding to these motifs, the co-activator mediates recruitment of substrates to the APC/C, which catalyzes their ubiquitylation. The co-activators themselves bind to the APC/C core via their C-box motif, a short, highly conserved motif that possibly interacts with the catalytic Apc2 subunit. Experimental evidence indicates that the C-box is essential for Cdc20 function and proteolysis of Clb2 by Cdh1, and is possibly involved in stimulating the catalytic activity of the APC/C.
ELMs with same func. site: LIG_APCC_Cbox_1  LIG_APCC_Cbox_2 
ELM Description:
The C-box motif is located in the N-terminal region of APC/C co-activators and is conserved among Cdc20-related proteins in Eukaryota. It mediates binding of the co-activators to the APC/C core, possibly to the catalytic Apc2 subunit. Removal of C-box from Cdh1 disrupts the ability of Cdh1 to trigger Clb2 proteolysis and overexpression of mutant Cdh1 lacking the C-box-containing region does not affect cell proliferation. Especially the residue in the second motif position, which is invariantly occupied by an arginine residue, seems to be important for binding Cdh1 to the APC/C in vitro and for APC/C function in vivo (Thornton,2006). Similarly, the C-box motif in Cdc20 was shown to be essential for proper protein function. Also, the arginine in the second position of the Cdc20 C-box is essential for motif function and seems to be crucial for viability as the charge-swap mutation of this residue is lethal (Thornton,2006). The binding site of the C-box on the APC/C has not yet been identified, but some evidence suggests that it might interact with the catalytic Apc2 subunit (Matyskiela,2009). This supports the idea that the APC/C co-activators to the APC/C are not only important for substrate recruitment, but are also involved in activating the catalytic activity of the complex, possibly through the interaction of their C-box motif with the APC/C catalytic core. This first variant of the motif is defined for Eukaryota except Fungi and Amoebozoa, due to a different conservation stringency of the last residue of the motif sequence. In most Eukaryota, this residue is invariantly an arginine, while in Fungi and Amoebozoa, this position is less conserved (DEG_APCC_Cbox_2). In addition, some Drosophila species tolerate a glutamate in the otherwise highly conserved first position that normally contains an aspartate. Similarly, Caenorhabditis species contain a glycine instead of proline or alanine in fifth position. These substitutions are not present in the Fungi and Amoebozoa specific variant.
Pattern: [DE]R[YFH][ILFVM][PAG].R
Pattern Probability: 0.0000015
Present in taxon: Eukaryota
Not represented in taxons: Amoebozoa Fungi
Interaction Domain:
TPR_1 (PF00515) Tetratricopeptide repeat (Stochiometry: 1 : 1)
o See 2 Instances for LIG_APCC_Cbox_1
o Abstract
The ubiquitylation pathway plays an important role in cell division as it mediates progression of the cell cycle by sequential targeting of important cell cycle regulators for proteasomal degradation. There are two E3 ubiquitin protein ligase complexes that regulate the cell cycle: the SCF (Skp1/Cullin/F-box) complex and the anaphase-promoting complex or cyclosome (APC/C) (Peters,2006, Castro,2005). The APC/C is a multiprotein complex that contains at least 13 different subunits, most of which are conserved in Eukaryotes. It consists of two subcomplexes that associate independently with the largest subunit Apc1. One is the catalytic core subcomplex that includes the cullin domain-containing subunit Apc2 and the RING domain-containing subunit Apc11. The second subcomplex mainly consists of tetratricopeptide repeat (TPR) domain-containing proteins including the Apc3/Cdc27, Apc8/Cdc23, Apc6/Cdc16, Apc5 and Apc7 subunits (Labit,2012). Several of the TPR-containing subunits form homodimers and are thus present in two copies in a single APC/C complex (Barford,2011, Primorac,2013).
Specific ubiquitylation of substrates requires association of the APC/C with a co-activator such as Cdc20/Fizzy or Cdh1/Fizzy-related, which are active at distinct phases of the cell cycle. These co-activators function as substrate-recruitment factors of the APC/C. They contain WD40 domain repeats, well known motif-binding modules that are folded as a 7-bladed beta-propeller. The WD40 repeats of APC/C co-activators recognize target proteins via short degradation motifs or degrons present in APC/C substrates. Well characterised degrons are the D-box (LIG_APCC_Dbox_1) and KEN-box (LIG_APCC_KENbox_2) motifs, which bind to distinct sites on the WD40 domain and are thought to preferentially interact with Cdc20 and Cdh1, respectively. However, efficient recruitment to and ubiquitylation by the APC/C likely depends on cooperative binding of multiple motifs (Chao,2012). In addition to substrate recognition, these co-activators are also required for activation of the ubiquitylation activity of the APC/C (Hayes,2006).
Binding of the co-activators to the APC/C is also mediated by multiple motifs, allowing multivalent cooperative binding (Matyskiela,2009). A Cdc20-specific motif has been described as a site for binding to the APC/C, possibly via the Apc8/Cdc23 subunit, and related to the specific role of this co-activator in the Spindle Assembly Checkpoint (SAC) (Izawa,2012). Both Cdc20 and Cdh1 share a C-terminal IR motif (LIG_APCC_TPR_1) that binds to the TPR repeats of the Apc3/Cdc27 subunit (Vodermaier,2003). In addition, both co-activators contain an internal C-box motif (LIG_APCC_Cbox_1 and LIG_APCC_Cbox_2), located in the N-terminal region, that most likely binds to the Apc2 subunit, and hence is possibly involved in stimulating the catalytic activity of the APC/C (da Fonseca,2011).
o 6 selected references:

o 8 GO-Terms:

o 2 Instances for LIG_APCC_Cbox_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q8AVG7 cdc20
85 91 PSRAGGDRFIPNRSAMQMDV TP 4 Xenopus laevis (African clawed frog)
Q12834 CDC20
77 83 PSKPGGDRYIPHRSAAQMEV TP 2 Homo sapiens (Human)
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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