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PDBsum entry 2nmb

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protein ligands links
Cell cycle/gene regulation PDB id
2nmb
Jmol
Contents
Protein chain
147 a.a. *
Ligands
ALA-TYR-ILE-GLY-
PRO-PTR-LEU
* Residue conservation analysis
PDB id:
2nmb
Name: Cell cycle/gene regulation
Title: Dnumb ptb domain complexed with a phosphotyrosine peptide, nmr, ensemble of structures.
Structure: Protein (numb protein). Chain: a. Fragment: ptb domain. Engineered: yes. Protein (gppy peptide). Chain: b. Engineered: yes. Other_details: chemically synthesized
Source: Drosophila melanogaster. Fruit fly. Organism_taxid: 7227. Gene: numb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes
NMR struc: 14 models
Authors: S.-C.Li,C.Zwahlen,S.J.F.Vincent,C.J.Mcglade,T.Pawson, J.D.Forman-Kay
Key ref:
S.C.Li et al. (1998). Structure of a Numb PTB domain-peptide complex suggests a basis for diverse binding specificity. Nat Struct Biol, 5, 1075-1083. PubMed id: 9846878 DOI: 10.1038/4185
Date:
29-Oct-98     Release date:   04-Nov-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P16554  (NUMB_DROME) -  Protein numb
Seq:
Struc:
 
Seq:
Struc:
556 a.a.
147 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 

 
DOI no: 10.1038/4185 Nat Struct Biol 5:1075-1083 (1998)
PubMed id: 9846878  
 
 
Structure of a Numb PTB domain-peptide complex suggests a basis for diverse binding specificity.
S.C.Li, C.Zwahlen, S.J.Vincent, C.J.McGlade, L.E.Kay, T.Pawson, J.D.Forman-Kay.
 
  ABSTRACT  
 
The phosphotyrosine-binding (PTB) domain of Numb, a protein involved in asymmetric cell division, has recently been shown to bind to the adapter protein Lnx through an LDNPAY sequence, to the Numb-associated kinase (Nak) through a sequence that does not contain an NPXY motif and to GP(p)Y-containing peptides obtained from library screening. We show here that these diverse peptide sequences bind with comparable affinities to the Numb PTB domain at a common binding site on the surface of the protein. The NMR structure of the Numb PTB domain in complex with a GPpY-containing peptide reveals a novel mechanism of binding with the peptide in a helical turn that does not hydrogen bond to the PTB domain beta-sheet. These results suggest that PTB domains can potentially have multiple modes of peptide recognition and provide a structural basis from which the multiple functions of the Numb PTB domain during asymmetric cell division could arise.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Solution structure of the dNumb PTB domain−GPpY peptide complex. a, Superposition of the 14 final structures. b, Schematic ribbon diagram of the backbone showing helices in green, -strands in yellow and the peptide in red. c, Interactions of the peptide with the PTB domain. Figure generated using MOLMOL^47.
Figure 3.
Figure 3. Structure-based alignment^34 of sequences of the dNumb, X11^14, Shc^8 and IRS-1^10 PTB domains, with residues of the dNumb PTB domain highlighted in green for helices and yellow for -strands. Residues in the PTB domains that have direct contacts to their target peptides are highlighted in red.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (1998, 5, 1075-1083) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20038578 G.A.Kyriazis, C.Belal, M.Madan, D.G.Taylor, J.Wang, Z.Wei, J.V.Pattisapu, and S.L.Chan (2010).
Stress-induced switch in Numb isoforms enhances Notch-dependent expression of subtype-specific transient receptor potential channel.
  J Biol Chem, 285, 6811-6825.  
20075861 M.J.Smith, W.R.Hardy, G.Y.Li, M.Goudreault, S.Hersch, P.Metalnikov, A.Starostine, T.Pawson, and M.Ikura (2010).
The PTB domain of ShcA couples receptor activation to the cytoskeletal regulator IQGAP1.
  EMBO J, 29, 884-896.  
  20567495 X.Xie, J.Hu, X.Liu, H.Qin, A.Percival-Smith, Y.Rao, and S.S.Li (2010).
NIP/DuoxA is essential for Drosophila embryonic development and regulates oxidative stress response.
  Int J Biol Sci, 6, 252-267.  
19952104 R.A.Neumüller, and J.A.Knoblich (2009).
Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer.
  Genes Dev, 23, 2675-2699.  
18657069 E.B.Sorensen, and S.D.Conner (2008).
AAK1 regulates Numb function at an early step in clathrin-mediated endocytosis.
  Traffic, 9, 1791-1800.  
17959648 E.Guney, N.Tuncbag, O.Keskin, and A.Gursoy (2008).
HotSprint: database of computational hot spots in protein interfaces.
  Nucleic Acids Res, 36, D662-D666.  
18599481 G.A.Kyriazis, Z.Wei, M.Vandermey, D.G.Jo, O.Xin, M.P.Mattson, and S.L.Chan (2008).
Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner: implications for Alzheimer disease pathogenesis.
  J Biol Chem, 283, 25492-25502.  
18650440 H.Li, S.Koshiba, F.Hayashi, N.Tochio, T.Tomizawa, T.Kasai, T.Yabuki, Y.Motoda, T.Harada, S.Watanabe, M.Inoue, Y.Hayashizaki, A.Tanaka, T.Kigawa, and S.Yokoyama (2008).
Structure of the C-terminal phosphotyrosine interaction domain of Fe65L1 complexed with the cytoplasmic tail of amyloid precursor protein reveals a novel peptide binding mode.
  J Biol Chem, 283, 27165-27178.
PDB codes: 1wgu 2roz 2ysz 2yt0 2yt1
18922798 K.F.Lau, W.M.Chan, M.S.Perkinton, E.L.Tudor, R.C.Chang, H.Y.Chan, D.M.McLoughlin, and C.C.Miller (2008).
Dexras1 Interacts with FE65 to Regulate FE65-Amyloid Precursor Protein-dependent Transcription.
  J Biol Chem, 283, 34728-34737.  
18843039 P.A.Keyel, J.R.Thieman, R.Roth, E.Erkan, E.T.Everett, S.C.Watkins, J.E.Heuser, and L.M.Traub (2008).
The AP-2 adaptor beta2 appendage scaffolds alternate cargo endocytosis.
  Mol Biol Cell, 19, 5309-5326.  
18753140 T.Mori, K.Kitano, S.Terawaki, R.Maesaki, Y.Fukami, and T.Hakoshima (2008).
Structural basis for CD44 recognition by ERM proteins.
  J Biol Chem, 283, 29602-29612.
PDB code: 2zpy
17473008 C.J.McCleverty, D.C.Lin, and R.C.Liddington (2007).
Structure of the PTB domain of tensin1 and a model for its recruitment to fibrillar adhesions.
  Protein Sci, 16, 1223-1229.
PDB code: 1wvh
17418793 Y.Zhou, J.B.Atkins, S.B.Rompani, D.L.Bancescu, P.H.Petersen, H.Tang, K.Zou, S.B.Stewart, and W.Zhong (2007).
The mammalian Golgi regulates numb signaling in asymmetric cell division by releasing ACBD3 during mitosis.
  Cell, 129, 163-178.  
16493689 A.M.Reugels, B.Boggetti, N.Scheer, and J.A.Campos-Ortega (2006).
Asymmetric localization of Numb:EGFP in dividing neuroepithelial cells during neurulation in Danio rerio.
  Dev Dyn, 235, 934-948.  
16982700 M.J.Smith, W.R.Hardy, J.M.Murphy, N.Jones, and T.Pawson (2006).
Screening for PTB domain binding partners and ligand specificity using proteome-derived NPXY peptide arrays.
  Mol Cell Biol, 26, 8461-8474.  
16002321 J.Chen, J.Xu, W.Zhao, G.Hu, H.Cheng, Y.Kang, Y.Xie, and Y.Lu (2005).
Characterization of human LNX, a novel ligand of Numb protein X that is downregulated in human gliomas.
  Int J Biochem Cell Biol, 37, 2273-2283.  
14670962 H.Qin, A.Percival-Smith, C.Li, C.Y.Jia, G.Gloor, and S.S.Li (2004).
A novel transmembrane protein recruits numb to the plasma membrane during asymmetric cell division.
  J Biol Chem, 279, 11304-11312.  
14990566 J.Nie, S.S.Li, and C.J.McGlade (2004).
A novel PTB-PDZ domain interaction mediates isoform-specific ubiquitylation of mammalian Numb.
  J Biol Chem, 279, 20807-20815.  
12906822 A.Farooq, L.Zeng, K.S.Yan, K.S.Ravichandran, and M.M.Zhou (2003).
Coupling of folding and binding in the PTB domain of the signaling protein Shc.
  Structure, 11, 905-913.
PDB codes: 1n3h 1oy2
12794636 A.Velyvis, J.Vaynberg, Y.Yang, O.Vinogradova, Y.Zhang, C.Wu, and J.Qin (2003).
Structural and functional insights into PINCH LIM4 domain-mediated integrin signaling.
  Nat Struct Biol, 10, 558-564.
PDB code: 1nyp
12606711 D.A.Calderwood, Y.Fujioka, J.M.de Pereda, B.García-Alvarez, T.Nakamoto, B.Margolis, C.J.McGlade, R.C.Liddington, and M.H.Ginsberg (2003).
Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling.
  Proc Natl Acad Sci U S A, 100, 2272-2277.  
12554651 K.Hamada, T.Shimizu, S.Yonemura, S.Tsukita, S.Tsukita, and T.Hakoshima (2003).
Structural basis of adhesion-molecule recognition by ERM proteins revealed by the crystal structure of the radixin-ICAM-2 complex.
  EMBO J, 22, 502-514.
PDB code: 1j19
12737822 P.C.Stolt, H.Jeon, H.K.Song, J.Herz, M.J.Eck, and S.C.Blacklow (2003).
Origins of peptide selectivity and phosphoinositide binding revealed by structures of disabled-1 PTB domain complexes.
  Structure, 11, 569-579.
PDB codes: 1ntv 1nu2
12620234 Q.Liu, D.Berry, P.Nash, T.Pawson, C.J.McGlade, and S.S.Li (2003).
Structural basis for specific binding of the Gads SH3 domain to an RxxK motif-containing SLP-76 peptide: a novel mode of peptide recognition.
  Mol Cell, 11, 471-481.
PDB code: 1h3h
12944396 Y.Zhou, J.Zhang, and M.L.King (2003).
Xenopus autosomal recessive hypercholesterolemia protein couples lipoprotein receptors with the AP-2 complex in oocytes and embryos and is required for vitellogenesis.
  J Biol Chem, 278, 44584-44592.  
11932255 D.A.Calderwood, B.Yan, J.M.de Pereda, B.G.Alvarez, Y.Fujioka, R.C.Liddington, and M.H.Ginsberg (2002).
The phosphotyrosine binding-like domain of talin activates integrins.
  J Biol Chem, 277, 21749-21758.  
11741908 D.D.Chang, B.Q.Hoang, J.Liu, and T.A.Springer (2002).
Molecular basis for interaction between Icap1 alpha PTB domain and beta 1 integrin.
  J Biol Chem, 277, 8140-8145.
PDB code: 1k11
11782429 J.Nie, M.A.McGill, M.Dermer, S.E.Dho, C.D.Wolting, and C.J.McGlade (2002).
LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation.
  EMBO J, 21, 93.  
11877385 K.S.Yan, M.Kuti, S.Yan, S.Mujtaba, A.Farooq, M.P.Goldfarb, and M.M.Zhou (2002).
FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors.
  J Biol Chem, 277, 17088-17094.  
11387212 B.A.Hocevar, A.Smine, X.X.Xu, and P.H.Howe (2001).
The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway.
  EMBO J, 20, 2789-2801.  
11412999 O.Zilian, C.Saner, L.Hagedorn, H.Y.Lee, E.Säuberli, U.Suter, L.Sommer, and M.Aguet (2001).
Multiple roles of mouse Numb in tuning developmental cell fates.
  Curr Biol, 11, 494-501.  
11090629 C.Dhalluin, K.S.Yan, O.Plotnikova, K.W.Lee, L.Zeng, M.Kuti, S.Mujtaba, M.P.Goldfarb, and M.M.Zhou (2000).
Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors.
  Mol Cell, 6, 921-929.
PDB code: 1xr0
10747019 C.Zwahlen, S.C.Li, L.E.Kay, T.Pawson, and J.D.Forman-Kay (2000).
Multiple modes of peptide recognition by the PTB domain of the cell fate determinant Numb.
  EMBO J, 19, 1505-1515.
PDB code: 1ddm
12760058 D.Durocher, S.J.Smerdon, M.B.Yaffe, and S.P.Jackson (2000).
The FHA domain in DNA repair and checkpoint signaling.
  Cold Spring Harb Symp Quant Biol, 65, 423-431.  
11080629 N.Blomberg, E.Baraldi, M.Sattler, M.Saraste, and M.Nilges (2000).
Structure of a PH domain from the C. elegans muscle protein UNC-89 suggests a novel function.
  Structure, 8, 1079-1087.
PDB code: 1fho
10629055 S.H.Ong, G.R.Guy, Y.R.Hadari, S.Laks, N.Gotoh, J.Schlessinger, and I.Lax (2000).
FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors.
  Mol Cell Biol, 20, 979-989.  
10461172 B.Margolis (1999).
The PTB Domain: The Name Doesn't Say It All.
  Trends Endocrinol Metab, 10, 262-267.  
10607674 J.D.Forman-Kay, and T.Pawson (1999).
Diversity in protein recognition by PTB domains.
  Curr Opin Struct Biol, 9, 690-695.  
10338211 K.E.Prehoda, D.J.Lee, and W.A.Lim (1999).
Structure of the enabled/VASP homology 1 domain-peptide complex: a key component in the spatial control of actin assembly.
  Cell, 97, 471-480.
PDB code: 1evh
10542412 N.Blomberg, E.Baraldi, M.Nilges, and M.Saraste (1999).
The PH superfold: a structural scaffold for multiple functions.
  Trends Biochem Sci, 24, 441-445.  
10607564 S.C.Li, G.Gish, D.Yang, A.J.Coffey, J.D.Forman-Kay, I.Ernberg, L.E.Kay, and T.Pawson (1999).
Novel mode of ligand binding by the SH2 domain of the human XLP disease gene product SAP/SH2D1A.
  Curr Biol, 9, 1355-1362.  
10411883 S.Dhe-Paganon, E.A.Ottinger, R.T.Nolte, M.J.Eck, and S.E.Shoelson (1999).
Crystal structure of the pleckstrin homology-phosphotyrosine binding (PH-PTB) targeting region of insulin receptor substrate 1.
  Proc Natl Acad Sci U S A, 96, 8378-8383.
PDB code: 1qqg
10551880 S.E.Dho, M.B.French, S.A.Woods, and C.J.McGlade (1999).
Characterization of four mammalian numb protein isoforms. Identification of cytoplasmic and membrane-associated variants of the phosphotyrosine binding domain.
  J Biol Chem, 274, 33097-33104.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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