The Eukaryote Linear Motif resource for Functional Sites in Proteins
Accession:
Functional site class:
PTB ligand
Functional site description:
Phosphotyrosine binding (PTB) domains recognize short peptides with a core Asn-X-X-Tyr motif preceded by a short peptide segment that docks by beta augmentation. The classical PTB domains bind the motif when it is phosphorylated on the Tyr residue. However other PTBs recognise essentially the same motif when unmodified.
ELMs with same func. site: LIG_PTB_Apo_2  LIG_PTB_Phospho_1 
ELM Description:
This classical version of the motif binds partly as an anti-parallel pseudo beta-strand forming extensive contacts with the beta5 strand and the C-terminal helix of the PTB domain. The peptide itself forms a type 1 beta-turn towards its distal end. This kink is formed by the NPxY motif. The beta-turn positions the tyrosine residue into a localized "anchoring" pocket, where much of the binding energy is concentrated. Additional binding affinity can be achieved by adding one or more hydrophobic residues N-terminal of the core motif at position -5 or nearby. Following the tyrosine residue the peptide turns away from the PTB domain, thereby preventing further contacts.
Pattern: (.[^P].NP.(Y))|(.[ILVMFY].N..(Y))
Pattern Probability: 0.0001352
Present in taxon: Metazoa
Interaction Domains:
PDB Structure: 2L1C
<a href="http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=2L1C" title="" target="_blank"><img src="/media/pdb.ico.png"/>2L1C</a>
o See 17 Instances for LIG_PTB_Phospho_1
o Abstract
Phosphotyrosine binding (PTB) domains are structurally conserved modules acting as adaptors or scaffolds to organize signaling complexes involved in a wide range of physiological processes. The PTB domain was first identified in the Shc signaling protein and subsequently in insulin receptor substrate 1 (IRS-1), as a modular domain that recognizes proteins with phosphorylated NPxY motifs. Structural studies have since divided phosphotyrosine-binding PTB domains into Shc-like and IRS-like based on the structure of their peptide binding grooves (Uhlik,2005). More recently, another category of PTB domains was identified as binding to non-phosphorylated (apo) NpxY/F motifs. These phosphotyrosine-independent Dab-like PTBs are thought to represent nearly 75% of proteins encoding PTB domains.
The general mode of peptide binding is conserved across all PTB domains. The PTB peptides are bound partly by beta-augmentation of several weakly conserved residues followed by the distal end containing the core consensus motif structured as a beta-turn. There are two fully conserved residues in the NxxY motif but with a strong preference for Proline at the -2 position while there is a weaker preference for a hydrophobic residue at position -5 (positions within PTB motifs are considered relative to the tyrosine residue at position 0.). The combination of both Pro -2 and hydrophobic -5 leads to higher affinity binding. The peptide backbone beta-augmentation further stabilizes the motif interactions. The core phosphorylation-independent motif is exactly the same as the aforementioned motif except with a Phe able to replace the Tyr residue (Nxx[YF]). In contrast to the pTyr motif, the apo-motif is less reliant on the Tyrosine at position 0 and instead relies on hydrophobic interactions and hydrogen bonding along the whole peptide. Furthermore, positions C-terminal of the core motif can contribute to the affinity of the binding. This is in contrast to the phosphorylated motif, that tends to branch away from the PTB surface in the residues following the pTyr.
The role of PTB domains is best characterized in the Shc adaptor protein. The presence of both PTB and SH2 domains allows Shc to bind numerous growth factors upon ligand stimulated activation. Upon binding to the activated receptor, Shc itself is phosphorylated and recruits a plethora of adaptor proteins, such as Grb2 and SOS1, leading to downstream pathway activation. To date, Shc is known to bind phosphotyrosine motifs on at least 15 different growth factors or cytokine receptors. Other PTB-containing proteins of the IRS (IRS1-4) and Dok (Dok1-5) families appear to function in a similar way (Uhlik,2005).
In contrast to the inducible nature of Shc/Irs/Dok PTB-mediated binding, almost all other PTB domains have specificities independent of phosphotyrosine. In fact, binding of many PTB domains is effectively inhibited by the presence of phosphotyrosine. Several of these Dab-like PTB containing proteins have been linked to Alzeimer's disease on the basis of their binding to amyloid precursor protein (Zhang,1997). These motifs are also strongly associated with endocytic signalling, in particular, receptors containing the motif [FY].NP.[FY] are often endocytosed via adaptor proteins such as Dab1 (Bonifacino,2003). The ability of a motif to bind different PTB domains depending on the phosphorylation state of its tyrosine residue means the motif can act as a phosphotyrosine switch. The NPxY motif in beta-integrin tails alters in this way to regulate the binding of tensin or talin within focal adhesions (Legate,2009).
It should also be noted that some, perhaps most, PTB domains have the ability to bind phospholipids. Such a dual role is also found with domains of the PDZ and PH domain families,. The simultaneous binding of phospholipids and peptide to PTB domains has been shown for non-phosphorylated motif binding Dab1-like domains (Howell,1999) whilst phosphopeptides and phospholipids have been reported to mutually compete for binding to the Shc PTB domain (Rameh,1997, Zhou,1995). However, in the later case the recruitment of Shc by the phospholipid precedes phosphopeptide binding (Ravichandran,1997). This ability to bind phospholipids may be crucial for the correct localization of PTB domains to the cytosolic side of cell membrane and in enabling cooperative signalling. Recent studies on the Talin PTB domain have revealed a variant motif with low similarity to the NxxY/F motif, the SPLH motif (Kong,2006). This variant is currently not represented in ELM.
o 9 selected references:

o 12 GO-Terms:

o 17 Instances for LIG_PTB_Phospho_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P03077 Middle T anti
MT_POVMA
244 250 RLRLPSLLSNPTYSVMRSHS TP 2 Murine polyomavirus strain A2
1 
1 
P04629 NTRK1
NTRK1_HUMAN
490 496 SGLQGHIIENPQYFSDACVH TP 3 Homo sapiens (Human)
1 
1 
Q61006 Musk
MUSK_MOUSE
547 553 ELLLDRLHPNPMYQRMPLLL TP 2 Mus musculus (House mouse)
1 
1 
P05106 ITGB3
ITB3_HUMAN
767 773 ARAKWDTANNPLYKEATSTF TP 4 Homo sapiens (Human)
3 
2 
Q07954 LRP1
LRP1_HUMAN
4467 4473 NGAMNVEIGNPTYKMYEGGE TP 2 Homo sapiens (Human)
P00533 EGFR
EGFR_HUMAN
1104 1110 PKRPAGSVQNPVYHNQPLNP TP 3 Homo sapiens (Human)
1 
1 
Q92835 INPP5D
SHIP1_HUMAN
909 915 SGSSITEIINPNYMGVGPFG TP 2 Homo sapiens (Human)
1 
1 
Q07954 LRP1
LRP1_HUMAN
4501 4507 DPDKPTNFTNPVYATLYMGG TP 5 Homo sapiens (Human)
2 
1 
P24394 IL4R
IL4RA_HUMAN
491 497 TETPLVIAGNPAYRSFSNSL TP 7 Homo sapiens (Human)
2 
1 
P05106 ITGB3
ITB3_HUMAN
779 785 NNPLYKEATSTFTNITYRGT TP 2 Homo sapiens (Human)
1 
4 
P35546 Ret
RET_MOUSE
1057 1063 RSLPSTWIENKLYGMSDPNW TP 2 Mus musculus (House mouse)
1 
1 
P14784 IL2RB
IL2RB_HUMAN
358 364 NHSLTSCFTNQGYFFFHLPD TP 3 Homo sapiens (Human)
1 
1 
P16144 ITGB4
ITB4_HUMAN
1590 1596 SVVVEDLLPNHSYVFRVRAQ TP 3 Homo sapiens (Human)
1 
1 
Q92835 INPP5D
SHIP1_HUMAN
1016 1022 PLTKPEMFENPLYGSLSSFP TP 4 Homo sapiens (Human)
1 
1 
P00533 EGFR
EGFR_HUMAN
1166 1172 KGSHQISLDNPDYQQDFFPK TP 3 Homo sapiens (Human)
1 
P21860 ERBB3
ERBB3_HUMAN
1322 1328 LEATDSAFDNPDYWHSRLFP TP 3 Homo sapiens (Human)
1 
1 
P06213 INSR
INSR_HUMAN
993 999 PLGPLYASSNPEYLSASDVF TP 4 Homo sapiens (Human)
3 
1 
Please cite: The Eukaryotic Linear Motif Resource ELM: 10 Years and Counting (PMID:24214962)

ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
feedback@elm.eu.org