PDBsum entry 5g05

Cell cycle

PDB id: 5g05

Contents

Protein chains

1569 a.a.

84 a.a.

524 a.a.

55 a.a.

56 a.a.

460 a.a.

25 a.a.

488 a.a.

723 a.a.

504 a.a.

182 a.a.

59 a.a.

604 a.a.

688 a.a.

492 a.a.

15 a.a.

26 a.a.

484 a.a.

Metals

_ZN ×3

PDB id:

5g05

Name:

Cell cycle

Title:

Cryo-em structure of combined apo phosphorylated apc

Structure:

Anaphase-promoting complex subunit 1. Chain: a. Synonym: apc1, cyclosome subunit 1, mitotic checkpoint regulator, testis-specific gene 24 protein. Engineered: yes. Anaphase-promoting complex subunit 11. Chain: b. Synonym: apc11, cyclosome subunit 11, hepatocellular carcinoma- associated ring finger protein.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: anapc1, tsg24. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: anapc11, hspc214. Gene: cdc23, anapc8. Gene: anapc15, c11orf51, hspc020.

Authors:

S.Zhang,L.Chang,C.Alfieri,Z.Zhang,J.Yang,S.Maslen,M.Skehel,D.Barford

Key ref:

S.Zhang et al. (2016). Molecular mechanism of APC/C activation by mitotic phosphorylation. Nature, 533, 260-264. PubMed id: 27120157 DOI: 10.1038/nature17973

Date:

16-Mar-16 Release date: 25-May-16

Protein chain

Q9H1A4  (APC1_HUMAN) -  Anaphase-promoting complex subunit 1 from Homo sapiens

Seq: 1944 a.a.

Struc: 1569 a.a.

Protein chain

Q9NYG5  (APC11_HUMAN) -  Anaphase-promoting complex subunit 11 from Homo sapiens

Seq: 84 a.a.

Struc: 84 a.a.

Protein chain

Q9UJX2  (CDC23_HUMAN) -  Cell division cycle protein 23 homolog from Homo sapiens

Seq: 597 a.a.

Struc: 524 a.a.

Protein chain

P60006  (APC15_HUMAN) -  Anaphase-promoting complex subunit 15 from Homo sapiens

Seq: 121 a.a.

Struc: 55 a.a.

Protein chain

Q96DE5  (APC16_HUMAN) -  Anaphase-promoting complex subunit 16 from Homo sapiens

Seq: 110 a.a.

Struc: 56 a.a.

Protein chain

P30260  (CDC27_HUMAN) -  Cell division cycle protein 27 homolog from Homo sapiens

Seq: 824 a.a.

Struc: 460 a.a.

Protein chain

Q8NHZ8  (CDC26_HUMAN) -  Anaphase-promoting complex subunit CDC26 from Homo sapiens

Seq: 85 a.a.

Struc: 25 a.a.

Protein chain

P30260  (CDC27_HUMAN) -  Cell division cycle protein 27 homolog from Homo sapiens

Seq: 824 a.a.

Struc: 488 a.a.

Protein chain

Q9UJX5  (APC4_HUMAN) -  Anaphase-promoting complex subunit 4 from Homo sapiens

Seq: 808 a.a.

Struc: 723 a.a.

Protein chains

Q13042  (CDC16_HUMAN) -  Cell division cycle protein 16 homolog from Homo sapiens

Seq: 620 a.a.

Struc: 504 a.a.

Protein chain

Q9UM13  (APC10_HUMAN) -  Anaphase-promoting complex subunit 10 from Homo sapiens

Seq: 185 a.a.

Struc: 182 a.a.

Protein chain

Q2NKV2  (APC13_BOVIN) -  Anaphase-promoting complex subunit 13 from Bos taurus

Seq: 74 a.a.

Struc: 59 a.a.

Protein chain

Q9UJX6  (ANC2_HUMAN) -  Anaphase-promoting complex subunit 2 from Homo sapiens

Seq: 822 a.a.

Struc: 604 a.a.

Protein chain

Q9UJX4  (APC5_HUMAN) -  Anaphase-promoting complex subunit 5 from Homo sapiens

Seq: 755 a.a.

Struc: 688 a.a.

Protein chain

Q9UJX2  (CDC23_HUMAN) -  Cell division cycle protein 23 homolog from Homo sapiens

Seq: 597 a.a.

Struc: 492 a.a.

Protein chain

No UniProt id for this chain

Struc: 15 a.a.

Protein chain

Q8NHZ8  (CDC26_HUMAN) -  Anaphase-promoting complex subunit CDC26 from Homo sapiens

Seq: 85 a.a.

Struc: 26 a.a.

Protein chains

Q9UJX3  (APC7_HUMAN) -  Anaphase-promoting complex subunit 7 from Homo sapiens

Seq: 565 a.a.

Struc: 484 a.a.

DOI no: 10.1038/nature17973

Nature 533:260-264 (2016)

PubMed id: 27120157

Molecular mechanism of APC/C activation by mitotic phosphorylation.

S.Zhang, L.Chang, C.Alfieri, Z.Zhang, J.Yang, S.Maslen, M.Skehel, D.Barford.

ABSTRACT

In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome segregation in mitosis and entry into the G1 phase. The catalytic activity of the APC/C and its ability to specify the destruction of particular proteins at different phases of the cell cycle are controlled by its interaction with two structurally related coactivator subunits, Cdc20 and Cdh1. Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 (refs 4-6). During mitosis, cyclin-dependent kinase (Cdk) and polo-like kinase (Plk) control Cdc20- and Cdh1-mediated activation of the APC/C. Hyperphosphorylation of APC/C subunits, notably Apc1 and Apc3, is required for Cdc20 to activate the APC/C, whereas phosphorylation of Cdh1 prevents its association with the APC/C. Since both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs, the mechanism underlying this differential regulation is unclear, as is the role of specific APC/C phosphorylation sites. Here, using cryo-electron microscopy and biochemical analysis, we define the molecular basis of how phosphorylation of human APC/C allows for its control by Cdc20. An auto-inhibitory segment of Apc1 acts as a molecular switch that in apo unphosphorylated APC/C interacts with the C-box binding site and obstructs engagement of Cdc20. Phosphorylation of the auto-inhibitory segment displaces it from the C-box-binding site. Efficient phosphorylation of the auto-inhibitory segment, and thus relief of auto-inhibition, requires the recruitment of Cdk-cyclin in complex with a Cdk regulatory subunit (Cks) to a hyperphosphorylated loop of Apc3. We also find that the small-molecule inhibitor, tosyl-l-arginine methyl ester, preferentially suppresses APC/C(Cdc20) rather than APC/C(Cdh1), and interacts with the binding sites of both the C-box and Ile-Arg tail motifs. Our results reveal the mechanism for the regulation of mitotic APC/C by phosphorylation and provide a rationale for the development of selective inhibitors of this state.