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 or -1 positions being strong determinants of specificity. The Trp-1 motif has a pattern such as W(ACGILV)$ (Ernst,2014, Stegmuller,2003), with the C-terminal hydrophobic residue forming a canonical interaction with the binding site in the PDZ domain, and tryptophan in position -1 forming hydrophobic interactions with the residues in the neighbouring β-sheet in the domain (1ZUB, 3R0H, 2LA8, 3SHW). Several less conserved positions in the motif may modulate affinity and specificity of the ligand domain interaction.
Pattern: .W[ACGILV]$
Pattern Probability: 0.0000037
Present in taxon: Metazoa
Interaction Domain:
PDZ (PF00595) PDZ domain (Also known as DHR or GLGF) (Stochiometry: 1 : 1)
PDB Structure: 1ZUB
o See 27 Instances for LIG_PDZ_Wminus1_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 8 selected references:

o 13 GO-Terms:

o 27 Instances for LIG_PDZ_Wminus1_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q99569 PKP4
PKP4_HUMAN
1190 1192 STKRPSYRAEQYPGSPDSWV TP 15 Homo sapiens (Human)
2 
Q9GZV5 WWTR1
WWTR1_HUMAN
398 400 PLFNDVESALNKSEPFLTWL TP 2 Homo sapiens (Human)
1 
Q16513 PKN2
PKN2_HUMAN
982 984 ILSEEEQEMFRDFDYIADWC TP 3 Homo sapiens (Human)
1 
Q1A244 vpu
VPU_SIVEK
77 79 DAEELANLLPPDRIDQDNWV TP 1 SIVcpz EK505
1 
Q9IDV3 vpu
VPU_HV1YB
72 74 DGDAEWLAILLSPDKLDNWV TP 1 HIV-1 N_YBF106
1 
A3EXD5 E
VEMP_BCHK5
80 82 RAAYVKFQESHPPYPPEDWV TP 1 Pipistrellus bat coronavirus HKU5
1 
A3EX99 E
VEMP_BCHK4
80 82 RNAYFKFQENRPPFPPEDWV TP 1 Tylonycteris bat coronavirus HKU4
1 
Q9UQB3 CTNND2
CTND2_HUMAN
1223 1225 PYSELNYETSHYPASPDSWV TP 15 Homo sapiens (Human)
3 
Q96DL1-3 NXPE2
NXPE2_HUMAN
363 365 SPDSASHVAGITSVQRHTWL TP 2 Homo sapiens (Human)
1 
Q8NHY3 GAS2L2
GA2L2_HUMAN
878 880 GLQPHWLNQAPLPPEEESWV TP 3 Homo sapiens (Human)
1 
O00192 ARVCF
ARVC_HUMAN
960 962 AVRLVDAVGDAKPQPVDSWV TP 10 Homo sapiens (Human)
2 
Q9Y5U5 TNFRSF18
TNR18_HUMAN
239 241 EEERGERSAEEKGRLGDLWV TP 2 Homo sapiens (Human)
Q96KN9 GJD4
CXD4_HUMAN
368 370 DPPASSSGAPHLRARKSEWV TP 2 Homo sapiens (Human)
Q8NGB0 Seven transmembrane helix receptor
Q8NGB0_HUMAN
1462 1464 ENPVSGKSICVSMDGNSSWV TP 2 Homo sapiens (Human)
Q6VVB1 NHLRC1
NHLC1_HUMAN
393 395 SLLVLDTASHSIKVYKVDWG TP 5 Homo sapiens (Human)
1 
Q9NTI7 INKA2
INKA2_HUMAN
295 297 CPKALEHSPSGFDINTAVWV TP 1 Homo sapiens (Human)
1 
Q8VHY0 Cspg4
CSPG4_MOUSE
2325 2327 ELLQFCRTPNPALRNGQYWV TP 3 Mus musculus (House mouse)
1 
Q9EPK5 Wwtr1
WWTR1_MOUSE
393 395 PLFNDVESALNKSEPFLTWL TP 3 Mus musculus (House mouse)
1 
P46937 YAP1
YAP1_HUMAN
502 504 DMESVLAATKLDKESFLTWL TP 3 Homo sapiens (Human)
P19334 trp
TRP_DROME
1273 1275 AAGGERGKSTVTGRMISGWL TP 7 Drosophila melanogaster (Fruit fly)
P36383 GJC1
CXG1_HUMAN
394 396 GSNKSTASSKSGDGKTSVWI TP 5 Homo sapiens (Human)
1 
A3RLX3 Kon
A3RLX3_DROME
2379 2381 SSPPSAPPTNPLLRRNQYWV TP 2 Drosophila melanogaster (Fruit fly)
1 
Q00657 Cspg4
CSPG4_RAT
2324 2326 ELLQFCRTPNPALRNGQYWV TP 2 Rattus norvegicus (Norway rat)
P98203 Arvcf
ARVC_MOUSE
960 962 SVRLVDAVGDTKPQPVDSWV TP 4 Mus musculus (House mouse)
P97445 Cacna1a
CAC1A_MOUSE
2366 2368 PRTARRGAHDAYSESEDDWC TP 3 Mus musculus (House mouse)
1 
Q00975 CACNA1B
CAC1B_HUMAN
2337 2339 LSSGGRARHSYHHPDQDHWC TP 3 Homo sapiens (Human)
1 
Q811U3 Erc1
RB6I2_RAT
946 948 SNQTNHKPSPDQDEEEGIWA TP 8 Rattus norvegicus (Norway rat)
1 
Please cite: The eukaryotic linear motif resource - 2018 update. (PMID:29136216)

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