The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
PDZ domain ligands
Functional site description:
The best characterised PDZ ligands (PBMs, PDZ-Binding Motifs) are short C-terminal peptides that bind in a surface groove of PDZ domains of proteins as a part of a variety of biological processes including cell signalling and synapse. Although there is a considerable literature on internal sequence peptide interactions, we are not currently representing internal PDZ-binding peptides in ELM.
ELMs with same func. site: LIG_PDZ_Class_1  LIG_PDZ_Class_2  LIG_PDZ_Class_3  LIG_PDZ_Wminus1_1 
ELM Description:
PDZ domains recognize short sequences at the carboxy terminus of target proteins. The terminal residue is apparently always hydrophobic with the -2 position being a strong determinant of specificity. The class 1 motif has a pattern such as (ST)X(VIL)*. We have made the terminal position more relaxed based on experimental binding data. However, probably not all PDZ domain instances can accept either A or F. Several less conserved positions in the motif may modulate affinity and specificity of the ligand domain interaction.
Pattern: ...[ST].[ACVILF]$
Pattern Probability: 0.0000725
Present in taxons: Eukaryota Homo sapiens Metazoa Mus musculus
Interaction Domain:
PDZ (PF00595) PDZ domain (Also known as DHR or GLGF) (Stochiometry: 1 : 1)
PDB Structure: 2EGN
o See 52 Instances for LIG_PDZ_Class_1
o Abstract
PDZ domains are ~90 residue globular protein modules that can be found in eukaryotic regulatory proteins. They are found in most eukaryotes but the domain family is hugely expanded in the Metazoa (over 250 PDZ domain instances are found in the Human proteome). Thus nearly all of the metazoan PDZ domain functions will be specific to this evolutionary lineage.

Most PDZ domain-containing proteins spend at least part of their time in membrane-associated complexes. Many PDZ ligands are themselves membrane proteins. Several PDZ domain containing proteins include multiple domain copies (MPDZ/MUPP1 and MAGI2 contain 13 and 6 PDZ domain instances respectively), acting as scaffolds, recruiting multiple PDZ domain binding proteins and facilitating the construction of large membrane-associated complexes. PDZ domains also co-occur regularly with other signalling/regulatory domains regulating many biological processes such as transport and signal transduction (Lee,2010). There is increasing evidence that some, ultimately perhaps most, PDZ domains also bind to phospholipid headgroups (Gallardo,2010). Thus PDZ domains have a role in assembly of signalling complexes at membrane locations determined by the appropriate lipid modification state. In large multiprotein complexes, they may do this in conjunction with other lipid-sampling domains such as C2, PH, PX and so forth to differentiate different membrane contexts. Peptide and lipid binding by PDZ domains has been found to be co-operative, enabling tight integration of lipid and protein regulatory signals.

For the carboxy-terminal binding motifs, position 0 (assigned to the C-terminal residue) is always hydrophobic while the class is determined by the position -2 (third last) residue. These two positions are the most buried in the bound complexes, hence they are strong specificity determinants. The sidechains of the ligand residues interact with a neighbouring α-helix in the PDZ domain, while the backbone of the ligand binds to the PDZ domain via β augmentation: it forms a β-strand with a neighbouring β-sheet in the domain (Chi,2012, Luck,2012). This mode of interaction is the most known but it doesn’t cover all PDZ binding motifs. For instance, the specificity of a PDZ ligand can also be defined by a tryptophan in position -1, which forms a hydrophobic interaction with the residues in the neighbouring β-sheet in the domain, without forming a β-strand. Apart from ligand positions 0, -1 and -2 being strong determinants of specificity, the neighbouring residues can undoubtedly contribute to specificity and affinity of the interactions (Ernst,2014). In ELM we have chosen relaxed motif patterns based on the solved PDZ complexes, so it is likely that any given peptide will only bind to a subset of the PDZ domains belonging to that class.
o 14 selected references:

o 6 GO-Terms:

o 52 Instances for LIG_PDZ_Class_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
B7ULW4 E2348C_0718
B7ULW4_ECO27
288 293 IMQSYHGGKQDLISVVLSKI TP 3 Escherichia coli O127:H6 str. E2348/69
Q7DB76 map
Q7DB76_ECO57
198 203 SEIKAITQNAILEHVQDTRL TP 5 Escherichia coli O157:H7
B7UMA0 map
B7UMA0_ECO27
198 203 SDIKALTEKAIADNVQDTRL TP 12 Escherichia coli O127:H6 str. E2348/69
B7UR60 E2348C_1442
B7UR60_ECO27
435 440 PHHNPSNYVDTVDIIQETRV TP 8 Escherichia coli O127:H6 str. E2348/69
P51790-2 CLCN3
CLCN3_HUMAN
861 866 TDEEREETEEEVYLLNSTTL TP 3 Homo sapiens (Human)
1 
1 
Q66T02 Plekhg5
PKHG5_MOUSE
1068 1073 QLYRIRTTLLLNSTLTASEV TP 2 Mus musculus (House mouse)
1 
1 
P22756-2 Grik1
GRIK1_RAT
900 905 SFTSILTCHQRRTQRKETVA TP 5 Rattus norvegicus (Norway rat)
1 
1 
O55207-3 Synj2
SYNJ2_RAT
1288 1293 FVRTVAAQRLTPVDASGSSV TP 9 Rattus norvegicus (Norway rat)
1 
1 
Q05586-4 GRIN1
NMDZ1_HUMAN
917 922 HPTDITGPLNLSDPSVSTVV TP 2 Homo sapiens (Human)
6 
Q9UQB8-4 BAIAP2
BAIP2_HUMAN
516 521 LDDYGARSMSSGSGTLVSTV TP 3 Homo sapiens (Human)
1 
Q01814 ATP2B2
AT2B2_HUMAN
1238 1243 SKSATSSSPGSPIHSLETSL TP 5 Homo sapiens (Human)
1 
Q9P0K1 ADAM22
ADA22_HUMAN
901 906 LPDEDKKVNRQSARLWETSI TP 3 Homo sapiens (Human)
1 
P97288-2 Htr4
5HT4R_MOUSE
382 387 HQELEKLPIHNDPESLESCF TP 4 Mus musculus (House mouse)
1 
3 
P06463 E6
VE6_HPV18
153 158 HSCCNRARQERLQRRRETQV TP 3 Human papillomavirus type 18
3 
P36762 L2
VL2_HPV49
516 521 SGDFYLHPSLRRRKRKRTYL TP 1 Human papillomavirus type 49
1 
P03524 G
VGLG_RABVE
519 524 QSGKIISSWESHKSGGETRL TP 3 Rabies virus ERA
1 
P03126 E6
VE6_HPV16
153 158 WTGRCMSCCRSSRTRRETQL TP 2 Human papillomavirus type 16
1 
P26672 VACWR172
A46_VACCW
235 240 YFEDDDSSTCSAVTDRETDV TP 1 Vaccinia virus WR
1 
P03409 tax
TAX_HTL1A
348 353 QISPGGLEPPSEKHFRETEV TP 4 Human T-cell lymphotrophic virus type 1 (strain ATK)
1 
Q9Q8T6 s147R
Q9Q8T6_RFVKA
282 287 HKISIYRCIMQADELMETDV TP 1 Rabbit fibroma virus (strain Kasza)
1 
Q9Q8F7 m147R
Q9Q8F7_MYXVL
283 288 HKISMYRCVMQADELLETDV TP 1 Myxoma virus (strain Lausanne)
1 
Q9DWF6 R35
Q9DWF6_RCMVM
516 521 PYSATGRRRGAVEGTRETSL TP 1 Rat cytomegalovirus Maastricht
1 
Q7TFX0 
Q7TFX0_RHCM6
141 146 IHFTVNNLILIFRVSEETQL TP 1 Rhesus cytomegalovirus strain 68-1
1 
P89079 E4
E4OR1_ADE09
120 125 VGTLLLERVIFPSVKIATLV TP 4 Human adenovirus 9
1 
Q9QUH6 Syngap1
SYGP1_RAT
1303 1308 KRLLDAQRGSFPPWVQQTRV TP 5 Rattus norvegicus (Norway rat)
2 
P13569 CFTR
CFTR_HUMAN
1475 1480 KPQIAALKEETEEEVQDTRL TP 7 Homo sapiens (Human)
1 
1 
P31424 Grm5
GRM5_RAT
1198 1203 SSPKYDTLIIRDYTQSSSSL TP 3 Rattus norvegicus (Norway rat)
1 
P46937-2 YAP1
YAP1_HUMAN
483 488 DMESVLAATKLDKESFLTWL TP 6 Homo sapiens (Human)
1 
P46937-3 YAP1
YAP1_HUMAN
449 454 DMESVLAATKLDKESFLTWL TP 5 Homo sapiens (Human)
Q9EPK5 Wwtr1
WWTR1_MOUSE
390 395 PLFNDVESALNKSEPFLTWL TP 4 Mus musculus (House mouse)
P46937 YAP1
YAP1_HUMAN
499 504 DMESVLAATKLDKESFLTWL TP 7 Homo sapiens (Human)
1 
Q495M9 USH1G
USH1G_HUMAN
456 461 AVRRRRQAMERPPALEDTEL TP 5 Homo sapiens (Human)
1 
O55043 Arhgef7
ARHG7_RAT
641 646 KLVRKVLKNMNDPAWDETNL TP 1 Rattus norvegicus (Norway rat)
1 
Q8TEU7 RAPGEF6
RPGF6_HUMAN
1596 1601 LGDVTDADSEADENEQVSAV TP 3 Homo sapiens (Human)
1 
P23634 ATP2B4
AT2B4_HUMAN
1236 1241 CNQVQLPQSDSSLQSLETSV TP 1 Homo sapiens (Human)
2 
6 
P48050 KCNJ4
IRK4_HUMAN
440 445 ERMQASLPLDNISYRRESAI TP 5 Homo sapiens (Human)
1 
1 
Q01344 IL5RA
IL5RA_HUMAN
415 420 IEVICYIEKPGVETLEDSVF TP 7 Homo sapiens (Human)
1 
Q9WTT6 Gda
GUAD_RAT
449 454 RNIEEVYVGGKQVVPFSSSV TP 1 Rattus norvegicus (Norway rat)
1 
P19490 Gria1
GRIA1_RAT
902 907 MQSIPCMSHSSGMPLGATGL TP 8 Rattus norvegicus (Norway rat)
1 
Q8R4T5 Grasp
GRASP_RAT
389 394 RLLKFIPGLNRSLEEEESQL TP 2 Rattus norvegicus (Norway rat)
1 
2 
Q86XX4 FRAS1
FRAS1_HUMAN
4002 4007 VKRLNLEVRVHNNLQDGTEV TP 2 Homo sapiens (Human)
1 
P97836 Dlgap1
DLGP1_RAT
987 992 SATESAESIEIYIPEAQTRL TP 1 Rattus norvegicus (Norway rat)
1 
Q13268 DHRS2
DHRS2_HUMAN
253 258 GESEDCAGIVSFLCSPDASY TP 1 Homo sapiens (Human)
1 
Q8QG92 dact1-b
DCT1B_XENLA
819 824 NLKKKILRFRSGSLKLMTTV TP 4 Xenopus laevis (African clawed frog)
1 
Q792Q4 Cript
CRIPT_RAT
96 101 ICAMCGKKVLDTKNYKQTSV TP 1 Rattus norvegicus (Norway rat)
1 
P35222 CTNNB1
CTNB1_HUMAN
776 781 LMDGLPPGDSNQLAWFDTDL TP 2 Homo sapiens (Human)
1 
2 
Q9H251 CDH23
CAD23_HUMAN
3349 3354 TPLHKLRDVIMETPLEITEL TP 1 Homo sapiens (Human)
1 
P11274 BCR
BCR_HUMAN
1266 1271 LEAIPAPDSKRQSILFSTEV TP 1 Homo sapiens (Human)
1 
1 
P09619 PDGFRB
PGFRB_HUMAN
1101 1106 EQLPDSGCPAPRAEAEDSFL TP 3 Homo sapiens (Human)
1 
1 
P07550 ADRB2
ADRB2_HUMAN
408 413 VPSDNIDSQGRNCSTNDSLL TP 3 Homo sapiens (Human)
1 
1 
Q61315 Apc
APC_MOUSE
2840 2845 ESSGAQSPKRHSGSYLVTSV TP 1 Mus musculus (House mouse)
1 
O88602 Cacng2
CCG2_MOUSE
318 323 QKDSKDSLHANTANRRTTPV TP 3 Mus musculus (House mouse)
1 
Please cite: The eukaryotic linear motif resource - 2018 update. (PMID:29136216)

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