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 2 motif has a pattern such as (VYF)X(VIL)*. We have made the conserved positions more relaxed based on experimental binding data. However, probably not all PDZ domain instances can accept either A or F at the terminal position. Several less conserved positions in the motif may modulate affinity and specificity of the ligand domain interaction.
Pattern: ...[VLIFY].[ACVILF]$
Pattern Probability: 0.0000789
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: 2KOH
o See 13 Instances for LIG_PDZ_Class_2
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 9 selected references:

o 6 GO-Terms:

o 13 Instances for LIG_PDZ_Class_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P97288-3 Htr4
5HT4R_MOUSE
366 371 NGSTHVLSFPLLFRNRPVPV TP 3 Mus musculus (House mouse)
1 
1 
Q9Y4C0 NRXN3
NRX3A_HUMAN
1638 1643 QQSSKSGHKKQKNKDREYYV TP 1 Homo sapiens (Human)
1 
Q07310 Nrxn3
NRX3A_RAT
1573 1578 QASSKSGHKKQKNKDKEYYV TP 1 Rattus norvegicus (Norway rat)
1 
P31431 SDC4
SDC4_HUMAN
193 198 SYDLGKKPIYKKAPTNEFYA TP 3 Homo sapiens (Human)
1 
P04626 ERBB2
ERBB2_HUMAN
1250 1255 TFKGTPTAENPEYLGLDVPV TP 2 Homo sapiens (Human)
1 
Q13136 PPFIA1
LIPA1_HUMAN
1197 1202 DGNVSGTQRLDSATVRTYSC TP 1 Homo sapiens (Human)
1 
P04921 GYPC
GLPC_HUMAN
123 128 LQGDPALQDAGDSSRKEYFI TP 2 Homo sapiens (Human)
1 
P19491 Gria2
GRIA2_RAT
878 883 QNFATYKEGYNVYGIESVKI TP 1 Rattus norvegicus (Norway rat)
1 
1 
Q811U3 Erc1
RB6I2_RAT
943 948 SNQTNHKPSPDQDEEEGIWA TP 2 Rattus norvegicus (Norway rat)
1 
P55284 Cdh5
CADH5_MOUSE
779 784 PRFKMLAELYGSDPQEELII TP 3 Mus musculus (House mouse)
1 
Q02410 APBA1
APBA1_HUMAN
832 837 KTMPAAMYRLLTAQEQPVYI TP 3 Homo sapiens (Human)
1 
1 
P49768 PSEN1
PSN1_HUMAN
462 467 ATDYLVQPFMDQLAFHQFYI TP 5 Homo sapiens (Human)
1 
P18827 SDC1
SDC1_HUMAN
305 310 PKQANGGAYQKPTKQEEFYA TP 3 Homo sapiens (Human)
1 
Please cite: The eukaryotic linear motif resource - 2018 update. (PMID:29136216)

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