ELM - Detail for DEG_COP1

Accession:	ELME000426
Functional site class:	COP1 E3 ligase binding degron motif
Functional site description:	COP1 was first identified by plant genetics to be involved in light-controlled development. COP1, also called RFWD2 is a RING finger protein with coiled-coil and WD 40 domains that associates with target proteins and participates in various biological functions. In plants it acts as a central switch for the transition from plant growth underground in darkness (etiolation) to growth under light exposure (photomorphogenesis). In animals it targets transcription factors that affect cell division and growth and may influence processes such as tumorigenesis, gluconeogenesis, and lipid metabolism. COP1 has ubiquitin ligase activity in both the plant and mammalian contexts. The WD repeat domain of COP1recognizes its target proteins through a destruction motif and directs them for protein ubiquitination and degradation. Proteins controlled by plant COP1 include PIF3, HY5, LAF1 and HFR1. In animals COP1 has been shown to regulate destruction of Jun/AP-1 and ETV1.
ELM Description:	The COP1 E3 ubiquitin ligase mediated protein recognition and subsequent proteasomal degradation is mediated by a destruction motif present in the target or adaptor proteins. It is the WD40 repeat domain of COP1 which acts as a substrate binding region. A conserved degron motif is present in interacting proteins. The solved structure with the TRIB1 degron shows that the motif binds across the central hole of the WD40 beta-propeller (5IGQ). The motif has a completely conserved VP (ValPro) hydrophobic core packing in a hydrophobic groove. In the best-studied cases, the VP core is preceded by a stretch of negative amino acids linked to VP by a spacer of two to three amino acids. There are four surface lysines on COP1 that are available to bind negative residues on the degron, but the single available structure does not show that they are all used. The Trib1 V358-P359 region provides a large energetic contribution to binding in a shallow binding pocket bounded by the COP1 residues F645, T618 and C559. The aromatic residues W517 and F645 form a ridge between the smaller VP-binding pocket and the larger central donut hole of the beta propeller. Following VP, there seems always to be a negatively charged residue and then a semi-conserved hydrophobic residue. Based on the plant and mammalian motifs where good biophysical data is available, the ELM motif has the pattern [STDE]{1,3}.{0,2}[SDE].{2,3}VP[SDE]G{0,1}[FLIMVYPA] but the motif is likely to be revised once degrons in other proteins receive biophysical characterisation. Phosphorylation plays an essential role in the ETS1 and ETS2 degrons. It is possible that some of the negatively charged residues can be replaced by hydrophobic interactions.
Pattern:	`[STDE]{1,3}.{0,2}[TSDE].{2,3}VP[STDE]G{0,1}[FLIMVYPA]`
Pattern Probability:	`0.0003906`
Present in taxons:	Metazoa Viridiplantae
Interaction Domain:	WD40 (PF00400) WD domain, G-beta repeat (Stochiometry: 1 : 1)

COP1 E3 ligase binding degron motif

COP1 was first identified by plant genetics to be involved in light-controlled development. COP1, also called RFWD2 is a RING finger protein with coiled-coil and WD 40 domains that associates with target proteins and participates in various biological functions. In plants it acts as a central switch for the transition from plant growth underground in darkness (etiolation) to growth under light exposure (photomorphogenesis). In animals it targets transcription factors that affect cell division and growth and may influence processes such as tumorigenesis, gluconeogenesis, and lipid metabolism. COP1 has ubiquitin ligase activity in both the plant and mammalian contexts. The WD repeat domain of COP1recognizes its target proteins through a destruction motif and directs them for protein ubiquitination and degradation. Proteins controlled by plant COP1 include PIF3, HY5, LAF1 and HFR1. In animals COP1 has been shown to regulate destruction of Jun/AP-1 and ETV1.

ELM Description:

The COP1 E3 ubiquitin ligase mediated protein recognition and subsequent proteasomal degradation is mediated by a destruction motif present in the target or adaptor proteins. It is the WD40 repeat domain of COP1 which acts as a substrate binding region. A conserved degron motif is present in interacting proteins. The solved structure with the TRIB1 degron shows that the motif binds across the central hole of the WD40 beta-propeller (5IGQ). The motif has a completely conserved VP (ValPro) hydrophobic core packing in a hydrophobic groove. In the best-studied cases, the VP core is preceded by a stretch of negative amino acids linked to VP by a spacer of two to three amino acids. There are four surface lysines on COP1 that are available to bind negative residues on the degron, but the single available structure does not show that they are all used. The Trib1 V358-P359 region provides a large energetic contribution to binding in a shallow binding pocket bounded by the COP1 residues F645, T618 and C559. The aromatic residues W517 and F645 form a ridge between the smaller VP-binding pocket and the larger central donut hole of the beta propeller. Following VP, there seems always to be a negatively charged residue and then a semi-conserved hydrophobic residue. Based on the plant and mammalian motifs where good biophysical data is available, the ELM motif has the pattern [STDE]{1,3}.{0,2}[SDE].{2,3}VP[SDE]G{0,1}[FLIMVYPA] but the motif is likely to be revised once degrons in other proteins receive biophysical characterisation. Phosphorylation plays an essential role in the ETS1 and ETS2 degrons. It is possible that some of the negatively charged residues can be replaced by hydrophobic interactions.

Pattern:

[STDE]{1,3}.{0,2}[TSDE].{2,3}VP[STDE]G{0,1}[FLIMVYPA]

Pattern Probability:

0.0003906

Present in taxons:

Metazoa Viridiplantae

Interaction Domain:

WD40 (PF00400) WD domain, G-beta repeat (Stochiometry: 1 : 1)

The Constitutive photomorphogenesis protein COP1 is a RING finger-type ubiquitin E3 ligase initially identified in Arabidopsis thaliana and other plants as a negative regulator of photomorphogenic development (Deng,1991). In darkness, it cooperates with COP9 signalosome in the nucleus, promoting the degradation of photomorphogenic-promoting transcription factors like HY5, HYH, HFR1 and LAF1 and drives the plant development in darkness toward skotomorphogenesis or etiolation (Sanchez-Barcelo,2016). Mammalian homologues of COP1 were ubiquitously expressed and located in both nucleus and cytoplasm as also seen in plants. More recently the human orthologue, huCOP1 (also named RFWD2), was characterised and it has been shown to act as both a tumor suppressor and promoter. It also acts as a regulator of the mechanism for the feeding-to-fasting transition. Its interaction with the oncogenic factors such as the c-Jun, JunD, ETV1 (and other ETS translocation variant transcription factors) leads to their ubiquitination and degradation by the proteasome, thus exerting tumor suppressor capability (Bianchi,2003; Vitari,2011). Gene fusions of ETV1 that delete the N-terminal COP1 binding degron are frequently found in prostate cancer (Vitari,2011). By contrast, COP1 has been reported to interact with the tumor suppressor factors p27 and p53, leading to increased tumorigenicity (Choi,2015). COP1 is also reported to regulate glucose metabolism by interacting with the proteins PTP1B and TORC2 (Sanchez-Barcelo,2016).

In both plants and animals, the best studied COP1 interacting partners all share a conserved motif consisting of a short stretch of negatively charged residues followed by the sequence VP[DE]. It has been demonstrated that COP1 recognises the degron motif via its WD40 repeats domain. This motif is seen in its substrate proteins as well as in the adaptor protein Tribbles (Uljon,2016; 5IGQ) which brings other proteins such as C/EBPalpha to COP1 for ubiquitination. The ETS1 and ETS2 sites are phosphodegrons, requiring Ser or Thr phosphorylation: But the ETS1 site can also be inhibited by phosphorylation on Tyr by Src, which may be important in triple negative breast cancer (Lu,2014). The relationship between huCOP1 and CSN signalosome (implicated in modulation of AP-1-dependent transcription) has to be further tested.

Biological Process:
Positive Regulation Of Cell Proliferation (also annotated in these classes: )
Regulation Of Transcription, Dna-Dependent (also annotated in these classes: )
Glucose Homeostasis (also annotated in class: )
Positive Regulation Of Proteasomal Ubiquitin-Dependent Protein Catabolic Process (also annotated in class: )
Negative Regulation Of Photomorphogenesis (also annotated in these classes: DEG_COP1 )
Cellular Compartment:
Cytosol (also annotated in these classes: )
Nucleus (also annotated in these classes: )
Molecular Function:
Protein Binding (also annotated in these classes: )
Ubiquitin Protein Ligase Binding (also annotated in these classes: )

Acc., Gene-, Name	Start	End	Subsequence	Logic	#Ev.	Organism	Notes
O24646 HY5 HY5_ARATH	38	46	GIESDEEIRRVPEFGGEAVG	TP	2	Arabidopsis thaliana (Thale cress)
P14921 ETS1 ETS1_HUMAN	273	283	SSQSSFNSLQRVPSYDSFDS	TP	2	Homo sapiens (Human)
P15036 ETS2 ETS2_HUMAN	301	311	NSQSSLLDVQRVPSFESFED	TP	2	Homo sapiens (Human)
P15036 ETS2 ETS2_HUMAN	46	56	SLNEEQTLQEVPTGLDSISH	TP	2	Homo sapiens (Human)
Q8W191 HYH HYH_ARATH	26	34	TEESDEELLMVPDMEAAGST	TP	4	Arabidopsis thaliana (Thale cress)
Q96RU8 TRIB1 TRIB1_HUMAN	354	361	DSEIGTSDQIVPEYQEDSDI	TP	6	Homo sapiens (Human)	5IGO 5IGQ 5IGO 5IGQ
P41161 ETV5 ETV5_HUMAN	66	73	EAQVPDDEQFVPDFQSDNLV	TP	1	Homo sapiens (Human)	1
P43268 ETV4 ETV4_HUMAN	74	81	AQVPDSDEQFVPDFHSENLA	TP	1	Homo sapiens (Human)	1
P50549 ETV1 ETV1_HUMAN	67	74	AQVPDNDEQFVPDYQAESLA	TP	4	Homo sapiens (Human)	1
Q9SID1 STH STH_ARATH	229	237	QRLEYRYDDEEEHFLVPDLG	TP	1	Arabidopsis thaliana (Thale cress)
P17535 JUND JUND_HUMAN	242	252	ALKDEPQTVPDVPSFGESPP	TP	1	Homo sapiens (Human)
P05412 JUN JUN_HUMAN	227	235	LQALKEEPQTVPEMPGETPP	TP	1	Homo sapiens (Human)

Acc., Gene-, Name

Start

End

Subsequence

Logic

#Ev.

Organism

Notes

O24646 HY5
HY5_ARATH

GIESDEEIRRVPEFGGEAVG

Arabidopsis thaliana (Thale cress)

P14921 ETS1
ETS1_HUMAN