The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
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:
Dab-like PTB domains bind to a non-modulated version of the NxxY motif and disfavour a phosphotyrosine residue at position 0. In contrast to the phosphorylated version of this motif, the anchoring pocket for the tyrosine is less critical for the overall peptide binding affinity. The majority of the binding affinity is therefore due to the large number of hydrophobic and hydrogen bonds contacts between the peptide and beta-sheet 5 of the PTB domain. This means that certain flanking residues can increase binding affinity including a polar residue at +1 can and hydrophobic position at -7.
Pattern: (.[^P].NP.[FY].)|(.[ILVMFY].N..[FY].)
Pattern Probability: 0.0003108
Present in taxon: Metazoa
Interaction Domains:
  • PID (PF00640) Phosphotyrosine interaction domain (PTB/PID) (Stochiometry: 1 : 1)
  • IRS (PF02174) PTB domain (IRS-1 type) (Stochiometry: 1 : 1)
PDB Structure: 3DXD
o See 19 Instances for LIG_PTB_Apo_2
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 19 Instances for LIG_PTB_Apo_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P05106 ITGB3
779 786 NNPLYKEATSTFTNITYRGT TP 1 Homo sapiens (Human)
Q8C351 Layn
374 381 SPDRMGRSKESGWVENEIYY TP 2 Mus musculus (House mouse)
P05107 ITGB2
760 767 DNPLFKSATTTVMNPKFAES TP 2 Homo sapiens (Human)
2536 2543 TNPTLVSVPNPVFGSDTFCE TP 3 Homo sapiens (Human)
Q9U485 Nak
1439 1446 QNSAKTGFSNMSFEDFPSDQ TP 2 Drosophila melanogaster (Fruit fly)
P16109 SELP
820 827 PHSHLGTYGVFTNAAFDPSP TP 2 Homo sapiens (Human)
178 185 LMTDEPGLDNPAYVSSAEDG TP 5 Homo sapiens (Human)
P01130 LDLR
822 829 KNINSINFDNPVYQKTTEDE TP 3 Homo sapiens (Human)
Q14114 LRP8
860 867 KNTKSMNFDNPVYRKTTEEE TP 3 Homo sapiens (Human)
Q07954 LRP1
4501 4508 DPDKPTNFTNPVYATLYMGG TP 6 Homo sapiens (Human)
Q9XWD6 ced-1
959 966 NNDEGREFQNPLYSRQSVFP TP 3 Caenorhabditis elegans
Q07954 LRP1
4467 4474 NGAMNVEIGNPTYKMYEGGE TP 5 Homo sapiens (Human)
P05106 ITGB3
767 774 ARAKWDTANNPLYKEATSTF TP 3 Homo sapiens (Human)
P05556 ITGB1
789 796 ENPIYKSAVTTVVNPKYEGK TP 4 Homo sapiens (Human)
P12023 App
756 763 SKMQQNGYENPTYKFFEQMQ TP 3 Mus musculus (House mouse)
P08592 App
756 763 SKMQQNGYENPTYKFFEQMQ TP 1 Rattus norvegicus (Norway rat)
P05067 APP
756 763 SKMQQNGYENPTYKFFEQMQ TP 8 Homo sapiens (Human)
P26010 ITGB7
772 779 QQLNWKQDSNPLYKSAITTT TP 2 Homo sapiens (Human)
P05556 ITGB1
777 784 MNAKWDTGENPIYKSAVTTV TP 2 Homo sapiens (Human)
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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