AiPD: Autoinhibited Protein Database

Q8K4S1

Gene name	Plce1 (Kiaa1516, Plce)
Protein name	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1
Names	EC 3.1.4.11 , Phosphoinositide phospholipase C-epsilon-1 , Phospholipase C-epsilon-1 , PLC-epsilon-1
Species	Mus musculus (Mouse)
KEGG Pathway	mmu:74055
EC number
Protein Class

Descriptions

Small GTPases couple their GDP/GTP structural cycle to cytosol/membrane alternation to function as versatile molecular switches in the cell. Membrane localization of their active, GTP-bound form is pivotal to their ability to propagate information, and this requires their post-translational modification by lipids.<br>Arf GTPases are modified by a myristate attached to their N-terminus, which is shielded by intramolecular interactions in their inactive state. The myristoylated N-terminus of Arf is autoinhibitory in solution and is displaced by membranes, priming Arf GTPases for activation by their GEFs. Replacement of the N-terminal myristate by a 6xHis-tag preserves autoinhibition, representing that membranes unlock the N-terminal region to facilitate subsequent activation.

Autoinhibitory domains (AIDs)

1522-1643 (X-Y linker) SS

Target domain	1373-1522 (PI-PLC X domain);1709-1826 (PI-PLC Y domain)
Relief mechanism	Ligand binding, Partner binding
Assay

AID

1522-1643 (X-Y linker)

Target domain

1373-1522 (PI-PLC X domain);1709-1826 (PI-PLC Y domain)

Relief mechanism

Ligand binding (Membrane association), Partner binding (G protein binding)

Assay

1973-1990 (C2-RA1 linker) SS

Target domain	1826-1851 (A cleft between TIM barrel and C2 domain)
Relief mechanism	Ligand binding, Partner binding
Assay

AID

1973-1990 (C2-RA1 linker)

Target domain

1826-1851 (A cleft between TIM barrel and C2 domain)

Relief mechanism

Ligand binding (Membrane association), Partner binding (G protein binding)

Assay

Accessory elements

No accessory elements

References

Muralidharan K et al. (2021) "Structure and regulation of phospholipase Cβ and ε at the membrane", Chemistry and physics of lipids, 235, 105050

Rugema NY et al. (2020) "Structure of phospholipase Cε reveals an integrated RA1 domain and previously unidentified regulatory elements", Communications biology, 3, 445

Autoinhibited structure

Activated structure

1 structures for Q8K4S1

Entry ID	Method	Resolution	Chain	Position	Source
AF-Q8K4S1-F1	Predicted				AlphaFoldDB

125 variants for Q8K4S1

Variant ID(s)	Position	Change	Diseaes Association	Provenance
rs253280628	24	S>L	No	EVA
rs3389530903	26	A>V	No	EVA
rs3389529609	27	E>D	No	EVA
rs3389539245	30	S>N	No	EVA
rs3389550371	34	S>L	No	EVA
rs3389529636	47	G>D	No	EVA
rs3389503599	59	K>E	No	EVA
rs213131754	79	E>D	No	EVA
rs235865647	82	C>G	No	EVA
rs254131378	86	S>P	No	EVA
rs223306819	86	S>Y	No	EVA
rs259059980	99	P>T	No	EVA
rs3389538330	134	C>S	No	EVA
rs3389445347	139	I>F	No	EVA
rs48812424	170	R>G	No	EVA
rs260044125	176	G>R	No	EVA
rs3389532184	178	H>Y	No	EVA
rs231779205	202	T>N	No	EVA
rs3389516414	204	S>*	No	EVA
rs3389493918	206	N>D	No	EVA
rs3389445407	217	T>S	No	EVA
rs262394709	223	Q>H	No	EVA
rs3389445354	223	Q>K	No	EVA
rs51753162	229	A>V	No	EVA
rs50967683	276	G>S	No	EVA
rs3389538285	283	G>D	No	EVA
rs30559618	295	N>S	No	EVA
rs50749515	351	C>R	No	EVA
rs3554102562	355	A>V	No	EVA
rs218680208	360	V>I	No	EVA
rs50029846	376	G>V	No	EVA
rs3554102478	390	R>C	No	EVA
rs581861627	390	R>H	No	EVA
rs246604299	391	L>Q	No	EVA
rs3389484754	404	R>I	No	EVA
rs3389530848	412	T>M	No	EVA
rs3389484827	421	T>S	No	EVA
rs49946911	434	E>G	No	EVA
rs3389530844	448	C>Y	No	EVA
rs3389538342	471	T>I	No	EVA
rs3408097056	492	M>I	No	EVA
rs52056572	498	L>P	No	EVA
rs3389493840	581	L>H	No	EVA
rs50946241	588	H>R	No	EVA
rs3389445403	630	K>Q	No	EVA
rs3389536621	631	C>*	No	EVA
rs3389536663	657	W>*	No	EVA
rs3389446252	667	T>I	No	EVA
rs3389536693	668	M>T	No	EVA
rs3389532185	671	L>V	No	EVA
rs221869272	682	V>L	No	EVA
rs3389553072	711	C>Y	No	EVA
rs3389532260	740	Y>N	No	EVA
rs3389493889	748	Q>*	No	EVA
rs3408837807	840	T>I	No	EVA
rs584345423	925	V>M	No	EVA
rs3389516392	941	V>M	No	EVA
rs3409283354	955	V>I	No	EVA
rs3407231787	956	Q>K	No	EVA
rs3389532230	1020	L>F	No	EVA
rs3389530834	1033	R>W	No	EVA
rs3412937779	1049	R>K	No	EVA
rs245015568	1135	T>S	No	EVA
rs264025823	1140	P>T	No	EVA
rs3389547189	1165	I>T	No	EVA
rs3407231805	1171	S>C	No	EVA
rs3407231840	1172	S>C	No	EVA
rs233449367	1181	M>L	No	EVA
rs243069838	1197	V>L	No	EVA
rs3389547196	1257	R>*	No	EVA
rs3389493852	1257	R>K	No	EVA
rs3389532181	1259	V>*	No	EVA
rs3389530364	1259	V>L	No	EVA
rs3389516363	1260	S>T	No	EVA
rs3409162672	1269	K>E	No	EVA
rs3389542027	1270	Q>H	No	EVA
rs3389538313	1310	L>H	No	EVA
rs3389530832	1338	V>I	No	EVA
rs3389484836	1423	D>V	No	EVA
rs3408174787	1436	T>P	No	EVA
rs3389536674	1447	V>M	No	EVA
rs3389538269	1453	S>C	No	EVA
rs3389550362	1460	L>M	No	EVA
rs3389547203	1463	I>N	No	EVA
rs3389530362	1468	N>S	No	EVA
rs3410769811	1487	G>*	No	EVA
rs3389493828	1500	F>Y	No	EVA
rs3389484782	1546	Q>L	No	EVA
rs3389538249	1558	A>P	No	EVA
rs244800560	1614	S>T	No	EVA
rs3389539240	1621	V>L	No	EVA
rs3389484803	1649	L>I	No	EVA
rs3389530297	1673	K>E	No	EVA
rs3389493919	1697	F>L	No	EVA
rs3389550359	1701	S>Y	No	EVA
rs3389536613	1750	R>H	No	EVA
rs3389542054	1799	D>H	No	EVA
rs3389539171	1829	S>G	No	EVA
rs214205915	1845	N>T	No	EVA
rs3389484748	1864	S>I	No	EVA
rs3389532216	1881	L>P	No	EVA
rs3389538320	1910	F>I	No	EVA
rs3389503622	1950	N>S	No	EVA
rs3389550424	1955	I>V	No	EVA
rs3389538300	1965	S>R	No	EVA
rs3408175672	1973	S>A	No	EVA
rs3389542033	1981	L>S	No	EVA
rs258938443	2034	C>R	No	EVA
rs3389530902	2070	I>T	No	EVA
rs3389539174	2076	S>N	No	EVA
rs3389530880	2081	E>D	No	EVA
rs3389536645	2085	G>S	No	EVA
rs3389539194	2109	I>F	No	EVA
rs3389503635	2150	C>G	No	EVA
rs3389553055	2186	K>M	No	EVA
rs3389446278	2186	K>N	No	EVA
rs3389553055	2186	K>R	No	EVA
rs3389547265	2188	S>P	No	EVA
rs3389516375	2194	D>Y	No	EVA
rs3409323289	2195	Q>H	No	EVA
rs215041587	2227	R>K	No	EVA
rs3389484807	2236	L>R	No	EVA
rs3389550356	2250	P>L	No	EVA
rs3389530301	2261	V>I	No	EVA
rs261776603	2273	S>A	No	EVA

No associated diseases with Q8K4S1

4 regional properties for Q8K4S1

Type	Name	Position	InterPro Accession
domain	Protein kinase domain	344 - 625	IPR000719
domain	Legume lectin domain	26 - 272	IPR001220
active_site	Serine/threonine-protein kinase, active site	464 - 476	IPR008271
binding_site	Protein kinase, ATP binding site	350 - 372	IPR017441

Functions

		Description
EC Number
Subcellular Localization
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

4 GO annotations of cellular component

Name	Definition
cytosol	The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
Golgi membrane	The lipid bilayer surrounding any of the compartments of the Golgi apparatus.
lamellipodium	A thin sheetlike process extended by the leading edge of a migrating cell or extending cell process; contains a dense meshwork of actin filaments.
plasma membrane	The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.

6 GO annotations of molecular function

Name	Definition
enzyme binding	Binding to an enzyme, a protein with catalytic activity.
guanyl-nucleotide exchange factor activity	Stimulates the exchange of GDP to GTP on a signaling GTPase, changing its conformation to its active form. Guanine nucleotide exchange factors (GEFs) act by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP), which is more abundant in the cell under normal cellular physiological conditions.
metal ion binding	Binding to a metal ion.
phosphatidylinositol phospholipase C activity	Catalysis of the reaction
phospholipase C activity	Catalysis of the reaction
small GTPase binding	Binding to a small monomeric GTPase.

11 GO annotations of biological process

Name	Definition
diacylglycerol biosynthetic process	The chemical reactions and pathways resulting in the formation of diacylglycerol, a glyceride in which any two of the R groups (positions not specified) are acyl groups while the remaining R group can be either H or an alkyl group.
epidermal growth factor receptor signaling pathway	The series of molecular signals initiated by binding of a ligand to the tyrosine kinase receptor EGFR (ERBB1) on the surface of a cell. The pathway ends with regulation of a downstream cellular process, e.g. transcription.
G protein-coupled receptor signaling pathway	The series of molecular signals initiated by a ligand binding to its receptor, in which the activated receptor promotes the exchange of GDP for GTP on the alpha-subunit of an associated heterotrimeric G-protein complex. The GTP-bound activated alpha-G-protein then dissociates from the beta- and gamma-subunits to further transmit the signal within the cell. The pathway begins with receptor-ligand interaction, and ends with regulation of a downstream cellular process. The pathway can start from the plasma membrane, Golgi or nuclear membrane.
intracellular signal transduction	The process in which a signal is passed on to downstream components within the cell, which become activated themselves to further propagate the signal and finally trigger a change in the function or state of the cell.
lipid catabolic process	The chemical reactions and pathways resulting in the breakdown of lipids, compounds soluble in an organic solvent but not, or sparingly, in an aqueous solvent.
phosphatidylinositol metabolic process	The chemical reactions and pathways involving phosphatidylinositol, any glycophospholipid in which a sn-glycerol 3-phosphate residue is esterified to the 1-hydroxyl group of 1D-myo-inositol.
phosphatidylinositol-mediated signaling	The series of molecular signals in which a cell uses a phosphatidylinositol-mediated signaling to convert a signal into a response. Phosphatidylinositols include phosphatidylinositol (PtdIns) and its phosphorylated derivatives.
phospholipase C-activating G protein-coupled receptor signaling pathway	A G protein-coupled receptor signaling pathway in which the signal is transmitted via the activation of phospholipase C (PLC) and a subsequent increase in the intracellular concentration of inositol trisphosphate (IP3) and diacylglycerol (DAG).
positive regulation of lamellipodium assembly	Any process that increases the rate, frequency or extent of the formation of a lamellipodium, a thin sheetlike extension of the surface of a migrating cell.
Ras protein signal transduction	The series of molecular signals within the cell that are mediated by a member of the Ras superfamily of proteins switching to a GTP-bound active state.
release of sequestered calcium ion into cytosol	The process in which calcium ions sequestered in the endoplasmic reticulum, Golgi apparatus or mitochondria are released into the cytosolic compartment.

29 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
P32383	PLC1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)	PR
Q1RML2	PLCZ1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1	Bos taurus (Bovine)	PR
P10895	PLCD1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1	Bos taurus (Bovine)	SS
Q2VRL0	PLCZ1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1	Gallus gallus (Chicken)	PR
Q86YW0	PLCZ1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1	Homo sapiens (Human)	PR
Q9BRC7	PLCD4	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4	Homo sapiens (Human)	SS
Q15111	PLCL1	Inactive phospholipase C-like protein 1	Homo sapiens (Human)	PR
P51178	PLCD1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1	Homo sapiens (Human)	EV
Q9UPR0	PLCL2	Inactive phospholipase C-like protein 2	Homo sapiens (Human)	PR
Q8N3E9	PLCD3	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3	Homo sapiens (Human)	SS
Q9P212	PLCE1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	Homo sapiens (Human)	SS
Q8K2J0	Plcd3	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3	Mus musculus (Mouse)	PR
Q8K394	Plcl2	Inactive phospholipase C-like protein 2	Mus musculus (Mouse)	PR
Q8R3B1	Plcd1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1	Mus musculus (Mouse)	SS
P51432	Plcb3	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3	Mus musculus (Mouse)	SS
Q62077	Plcg1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1	Mus musculus (Mouse)	SS
A3KGF7	Plcb2	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2	Mus musculus (Mouse)	PR
Q9Z1B3	Plcb1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1	Mus musculus (Mouse)	SS
Q7YRU3	PLCZ	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1	Sus scrofa (Pig)	PR
P10688	Plcd1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1	Rattus norvegicus (Rat)	SS
Q99P84	Plce1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	Rattus norvegicus (Rat)	EV
Q39032	PLC1	Phosphoinositide phospholipase C 1	Arabidopsis thaliana (Mouse-ear cress)	PR
Q56W08	PLC3	Phosphoinositide phospholipase C 3	Arabidopsis thaliana (Mouse-ear cress)	PR
Q6NMA7	PLC9	Phosphoinositide phospholipase C 9	Arabidopsis thaliana (Mouse-ear cress)	PR
Q8GV43	PLC6	Phosphoinositide phospholipase C 6	Arabidopsis thaliana (Mouse-ear cress)	PR
Q944C2	PLC5	Phosphoinositide phospholipase C 5	Arabidopsis thaliana (Mouse-ear cress)	PR
Q9STZ3	PLC8	Phosphoinositide phospholipase C 8	Arabidopsis thaliana (Mouse-ear cress)	PR
Q944C1	PLC4	Phosphoinositide phospholipase C 4	Arabidopsis thaliana (Mouse-ear cress)	PR
A5D6R3	plcd3a	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3-A	Danio rerio (Zebrafish) (Brachydanio rerio)	PR

10	20	30	40	50	60
MGQLIAKLMR	IFGSQEHKVI	IVGLDNAGKT	TILYQFLTNE	VVHTCSTIGS	NVEEIVLRKT
70	80	90	100	110	120
HFLMWDLGGQ	EALRSTWDTY	YSNAEFVILV	IDSTDRNRLL	TTREELYKML	AHEALQNASV
130	140	150	160	170
LIFANKQDVK	DSMTTAEISQ	FLTLSAIKDH	PWHIQGCCAL	TGEGLPAGLQ	WMQAQATAN