The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
APCC_TPR-docking motifs
Functional site description:
The Anaphase Promoting Complex or Cyclosome (APC/C) E3 ubiquitin ligase is an important regulator of the cell cycle. Timely activation and substrate specificity is mainly controlled by the co-activator proteins Cdc20 and Cdh1, which recognize short destruction motifs present in APC/C substrates (including LIG_APCC_Dbox_1 and LIG_APCC_KENbox_2 degrons). Targeting of these motifs to the co-activators recruits the substrates to the APC/C, which catalyzes their ubiquitylation and thereby marks them for subsequent proteasomal degradation. The co-activators themselves, and also the APC/C subunit Doc1/APC10, bind to the APC/C core through a short C-terminal motif that interacts with tetratricopeptide repeat (TPR) regions present in some of the APC/C subunits. In addition, some APC/C substrates also contain this motif and hence they can bind directly to the APC/C, independently of co-activators.
ELM Description:
The “IR” motif is located at the C-terminal end of APC/C-binding proteins. It binds to tetratricopeptide repeat (TPR) regions, which are present in the APC/C subunits Apc3, Apc8, Apc6 and the Vertebrate-specific Apc7. Experimental evidence suggests Apc3 is the main binding partner (Matyskiela,2009). The C-terminal residue is invariantly arginine. In the Apc10 subunit and in the mitotic co-activators Cdc20 and Cdh1 the preceding hydrophobic residue is predominantly isoleucine, although in some taxa this is replaced by leucine or methionine. In addition, several meiotic APC/C regulators contain a methionine in this position. The APC/C substrates Nek2 kinase and kinesin-like protein Kif18A contain methionine and leucine, respectively, in the hydrophobic position, but again isoleucine, leucine and methionine seem to be allowed in both cases. It should be noted that, for most of these proteins, taxa can be found where this position is occupied by another hydrophobic residue, mainly valine but sometimes also phenylalanine, but these are rather rare, not studied and occur in taxa prone to sequencing errors, hence they are currently not included in the motif model. Concerning motif function, the following model has been inferred (Izawa,2011, Barford,2011). During active SAC, Cdc20 is bound to Apc8, leaving the “IR” binding site on Apc3 available for binding of substrates such as Nek2. This allows its ubiquitylation during prometaphase, independent of direct binding to Cdc20. However, binding of Cdc20 to the APC/C is still required, as it activates the APC/C. When the SAC is inactive, Cdc20 is repositioned and its “IR” motif binds to one subunit of the Apc3/Cdc27 homodimer, while the “IR” motif of Apc10 binds the second subunit. This aligns Cdc20 and Apc10/Doc1 to form the receptor site for D-box motifs.
Pattern: .[ILM]R$
Pattern Probability: 0.0000136
Present in taxon: Eukaryota
Interaction Domain:
TPR (SM00028) Tetratricopeptide repeats. (Stochiometry: 1 : 1)
o See 22 Instances for DEG_APCC_TPR_1
o Abstract
Progress through the cell division cycle depends on ubiquitin-mediated proteasomal degradation of specific proteins at specific times. An essential regulator of this process is the Anaphase Promoting Complex or Cyclosome (APC/C), an E3 ubiquitin ligase that catalyses covalent linking of polyubiquitin chains to crucial cell cycle regulators and thereby marks them for 26S proteasome-mediated proteolysis. The APC/C is a multiprotein complex that contains at least 13 different subunits, most of which are conserved in Eukaryotes. These include the catalytic Apc2 and Apc11 subunits, the tetratricopeptide repeat (TPR)-containing Apc3/Cdc27, Apc8/Cdc23 and Apc6/Cdc16 subunits, which form homodimers and are thus present in two copies in a single APC/C complex, and the Apc10/Doc1 subunit, which is involved in substrate recognition (Barford,2011, Primorac,2013).
Timely and sequential targeting of its substrates for degradation depends on tight temporal regulation of the activity and substrate specificity of the APC/C. This regulation is partly mediated by the two mitotic co-activators Cdc20 and Cdh1, which activate the APC/C at different stages of the cell cycle: Cdc20 during early mitosis and Cdh1 during late mitosis and G1 phase. They both contain a WD40-repeat domain, which acts as a binding platform for APC/C substrates that contain D-box (LIG_APCC_Dbox_1) or KEN-box (LIG_APCC_KENbox_2) degradation motifs. D-box and KEN-box motifs bind to distinct sites on the WD40-repeat 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, the specificity and affinity for D-box-containing substrates is enhanced by cooperative binding of the motif with co-activator and Apc10/Doc1, which together form a multivalent co-receptor for the D-box (Matyskiela,2009, da Fonseca,2011). Another important determinant of APC/C activity and specificity is the Mitotic Checkpoint Complex (MCC), which imposes the Spindle Assembly Checkpoint (SAC) to ensure that chromosomes are correctly attached to the spindle apparatus before chromosome segregation is initiated. The MCC includes Cdc20 and binds to the APC/C to inhibit recruitment of substrates by Cdc20, thereby preventing metaphase to anaphase transition. Important substrates that are stabilised by the SAC are securin and B-type cyclins, which both inhibit the separase activity that is required for chromosome segregation (Barford,2011).
Binding of the co-activators to the APC/C is also mediated by multiple motifs, allowing multivalent cooperative binding (Matyskiela,2009). Only recently, a Cdc20-specific motif was 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 SAC (Izawa,2012). Both Cdc20 and Cdh1 share 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 (da Fonseca,2011). In addition, both co-activators contain an IR sequence at their extreme C-terminus that interacts with the TPRs of the Apc3/Cdc27 subunit (Vodermaier,2003). This C-terminal sequence is also present in the Apc10/Doc1 subunit, where it also mediates binding to Apc3/Cdc27 (Wendt,2001). In addition, some substrates, including Nek2 kinase and the kinesin-like protein Kif18A, use a similar C-terminal hydrophobic-arginine motif to bind directly to the APC/C, probably also via Apc3/Cdc27, independently of a co-activator (Barford,2011, Sedgwick,2013).
o 8 selected references:

o 10 GO-Terms:

o 22 Instances for DEG_APCC_TPR_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P78972 slp1
486 488 DHVKRPIPITKTPSSSITIR U 2 Schizosaccharomyces pombe 972h-
Q6UZ79 B-type cell cycle switch protein ccs52B
469 471 KTPAPVKDTGLWSLGRTQIR U 2 Medicago truncatula (Barrel medic)
Q9M7I2 CCS52
473 475 KSQNTESEIGALSLGRTTIR TP 2 Medicago truncatula (Barrel medic)
O13286 srw1
554 556 KSKHSASTMSSPFDPTMKIR U 2 Schizosaccharomyces pombe 972h-
Q9W1F6 fzr2
449 451 TKQKISKEPNSVLRLFKGIR U 2 Drosophila melanogaster (Fruit fly)
P53197 CDH1
564 566 KPKAKVQPNSLIFDAFNQIR TP 13 Saccharomyces cerevisiae S288c
P26309 CDC20
608 610 KNSSEIHTRRPSSTSQYLIR TP 12 Saccharomyces cerevisiae (Baker"s yeast)
494 496 RSTKVKWESVSVLNLFTRIR TP 7 Homo sapiens (Human)
O94423 mfr1
419 421 TLRFWKLFNKKPKEESTLIR U 1 Schizosaccharomyces pombe 972h-
Q960N3 cort
481 483 KQEQKAKDKCSSLSLYKGIR TP 3 Drosophila melanogaster (Fruit fly)
P50082 AMA1
591 593 GSNIIEYMEGIETTHNKRIR TP 2 Saccharomyces cerevisiae S288c
183 185 SIGKFPRCTTIDFMMYRSIR TP 4 Homo sapiens (Human)
Q12834 CDC20
497 499 RREREKASAAKSSLIHQGIR TP 3 Homo sapiens (Human)
479 481 KMQTPVKDTGLWSLGRTQIR TP 2 Arabidopsis thaliana (Thale cress)
481 483 KSQNTDSEIGSSFFGRTTIR TP 2 Arabidopsis thaliana (Thale cress)
Q3E906 AT5G27570
409 411 QSPDGCTVASAAGDETLRLW TP 2 Arabidopsis thaliana (Thale cress)
Q9SZA4 F17M5.30
455 457 AKKAAPKAVSEPFSHVNRIR TP 4 Arabidopsis thaliana (Thale cress)
Q9S7I8 F17M5.20
445 447 AKKAAPKAVAEPFSHVNRIR TP 4 Arabidopsis thaliana (Thale cress)
P41005 mes1
99 101 HSSHKQPSKARSPNPLLSMR U 1 Schizosaccharomyces pombe 972h-
Q9M2R1 T10K17.70
241 243 TPQAKREEREKRVRTLMTMR TP 2 Arabidopsis thaliana (Thale cress)
896 898 KINPSMVRKFGRNISKGNLR TP 7 Homo sapiens (Human)
P51955 NEK2
443 445 ALSDIEKNYQLKSRQILGMR TP 13 Homo sapiens (Human)
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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