Recruitment of the inhibitor Cand1 to the cullin substrate adaptor site mediates interaction to the neddylation site.
Cand1 inhibits cullin RING ubiquitin ligases by binding unneddylated cullins. The Cand1 N-terminus blocks the cullin neddylation site, whereas the C-terminus inhibits cullin adaptor interaction. These Cand1 binding sites can be separated into two functional polypeptides which bind sequentially. C-terminal Cand1 can directly bind to unneddylated cullins in the nucleus without blocking the neddylation site. The smaller N-terminal Cand1 cannot bind to the cullin neddylation region without C-terminal Cand1. The separation of a single cand1 into two independent genes represents the in vivo situation of the fungus Aspergillus nidulans, where C-terminal Cand1 recruits smaller N-terminal Cand1 in the cytoplasm. Either deletion results in an identical developmental and secondary metabolism phenotype in fungi, which resembles csn mutants deficient in the COP9 signalosome (CSN) deneddylase. We propose a two-step Cand1 binding to unneddylated cullins which initiates at the adaptor binding site and subsequently blocks the neddylation site after CSN has left.
Institute of Microbiology and Genetics, Georg-August-Universität, D-37077 Göttingen, Germany.
Kerstin
K
Helmstaedt
Elke U
EU
Schwier
Martin
M
Christmann
Krystyna
K
Nahlik
Mieke
M
Westermann
Rebekka
R
Harting
Stephanie
S
Grond
Silke
S
Busch
Gerhard H
GH
Braus
D019677:Artificial Gene Fusion; D001233:Aspergillus nidulans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D044842:Cullin Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism
D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D005656:Fungal Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D014452:Ubiquitins