PDBsum entry 1nf1

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protein links
Signaling protein PDB id
Protein chain
260 a.a. *
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: The gap related domain of neurofibromin
Structure: Protein (neurofibromin). Chain: a. Fragment: gap related domain. Synonym: nf1-333. Engineered: yes. Other_details: see ref.5 for details
Source: Homo sapiens. Human. Organism_taxid: 9606. Cellular_location: cytosol. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: s. Ref. 4
2.50Å     R-factor:   0.266     R-free:   0.369
Authors: K.Scheffzek,M.R.Ahmadian,L.Wiesmueller,W.Kabsch,P.Stege, F.Schmitz,A.Wittinghofer
Key ref:
K.Scheffzek et al. (1998). Structural analysis of the GAP-related domain from neurofibromin and its implications. EMBO J, 17, 4313-4327. PubMed id: 9687500 DOI: 10.1093/emboj/17.15.4313
08-Jul-98     Release date:   20-Jul-99    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P21359  (NF1_HUMAN) -  Neurofibromin
2839 a.a.
260 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   1 term 
  Biological process     signal transduction   3 terms 
  Biochemical function     GTPase activator activity     2 terms  


DOI no: 10.1093/emboj/17.15.4313 EMBO J 17:4313-4327 (1998)
PubMed id: 9687500  
Structural analysis of the GAP-related domain from neurofibromin and its implications.
K.Scheffzek, M.R.Ahmadian, L.Wiesmüller, W.Kabsch, P.Stege, F.Schmitz, A.Wittinghofer.
Neurofibromin is the product of the NF1 gene, whose alteration is responsible for the pathogenesis of neurofibromatosis type 1 (NF1), one of the most frequent genetic disorders in man. It acts as a GTPase activating protein (GAP) on Ras; based on homology to p120GAP, a segment spanning 250-400 aa and termed GAP-related domain (NF1GRD; 25-40 kDa) has been shown to be responsible for GAP activity and represents the only functionally defined segment of neurofibromin. Missense mutations found in NF1 patients map to NF1GRD, underscoring its importance for pathogenesis. X-ray crystallographic analysis of a proteolytically treated catalytic fragment of NF1GRD comprising residues 1198-1530 (NF1-333) of human neurofibromin reveals NF1GRD as a helical protein that resembles the corresponding fragment derived from p120GAP (GAP-334). A central domain (NF1c) containing all residues conserved among RasGAPs is coupled to an extra domain (NF1ex), which despite very limited sequence homology is surprisingly similar to the corresponding part of GAP-334. Numerous point mutations found in NF1 patients or derived from genetic screening protocols can be analysed on the basis of the three-dimensional structural model, which also allows identification of the site where structural changes in a differentially spliced isoform are to be expected. Based on the structure of the complex between Ras and GAP-334 described earlier, a model of the NF1GRD-Ras complex is proposed which is used to discuss the strikingly different properties of the Ras-p120GAP and Ras-neurofibromin interactions.
  Selected figure(s)  
Figure 1.
Figure 1 Aspects of structure determination (stereo views). (A) Experimental MIR map, (contoured at 20% of the maximum) calculated with phases derived from the heavy atom model. The C[ ]-traces of the central (blue) and extra domain (yellow) are included. (B) Segment of the 2F[o]-F[c] map (contoured at 1.2 ) covering the C-terminal half of helix 7[c] and the variable loop (L6[c]) after structure refinement with the model included. A segment of a neighbouring molecule covering residues 1373 -1377 [see (C)] is shown in pink. (C) Section comparing NF1GRD (blue) and GAP-334 (red) in the region of the loop preceding 6[c], showing a three residue insertion in GAP-334 (see Figure 2B). Arginine 1375 contacts the N-terminal region of the finger loop. The corresponding situation is found for Lys884 in GAP-334.
Figure 5.
Figure 5 On the Ras -NF1GRD interaction. (A) Hypothetical complex between Ras (grey) and NF1-333 (blue), modelled according to the structure of the Ras-GDP -AlF[3] -GAP-334 complex. Segments coloured in red are derived from the GAP-334 model and correspond to regions of presumed high mobility in NF1GRD. SwI, Switch I; SwII, Switch II. Positions of patient mutations affecting the interaction with Ras are indicated by grey spheres. (B) Stereo view of the region covering part of a hydrophobic core stabilization of which involves residues derived from the finger loop and from 6[c] (see text).
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (1998, 17, 4313-4327) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23178454 R.Baker, S.M.Lewis, A.T.Sasaki, E.M.Wilkerson, J.W.Locasale, L.C.Cantley, B.Kuhlman, H.G.Dohlman, and S.L.Campbell (2013).
Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function.
  Nat Struct Mol Biol, 20, 46-52.  
20927530 A.L.Gabriele, M.Ruggieri, A.Patitucci, A.Magariello, F.L.Conforti, R.Mazzei, M.Muglia, C.Ungaro, G.Di Palma, L.Citrigno, W.Sproviero, A.Gambardella, and A.Quattrone (2011).
A novel NF1 gene mutation in an Italian family with neurofibromatosis type 1.
  Childs Nerv Syst, 27, 635-638.  
21089070 S.Welti, S.Kühn, I.D'Angelo, B.Brügger, D.Kaufmann, and K.Scheffzek (2011).
Structural and biochemical consequences of NF1 associated nontruncating mutations in the Sec14-PH module of neurofibromin.
  Hum Mutat, 32, 191-197.
PDB codes: 3p7z 3peg 3pg7
20635345 R.Lam, V.Romanov, K.Johns, K.P.Battaile, J.Wu-Brown, J.L.Guthrie, R.P.Hausinger, E.F.Pai, and N.Y.Chirgadze (2010).
Crystal structure of a truncated urease accessory protein UreF from Helicobacter pylori.
  Proteins, 78, 2839-2848.
PDB code: 3cxn
19479903 F.Kweh, M.Zheng, E.Kurenova, M.Wallace, V.Golubovskaya, and W.G.Cance (2009).
Neurofibromin physically interacts with the N-terminal domain of focal adhesion kinase.
  Mol Carcinog, 48, 1005-1017.  
19717441 H.He, T.Yang, J.R.Terman, and X.Zhang (2009).
Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration.
  Proc Natl Acad Sci U S A, 106, 15610-15615.
PDB code: 3ig3
18772345 M.Hirosawa-Takamori, D.Ossipov, S.V.Novoselov, A.A.Turanov, Y.Zhang, V.N.Gladyshev, A.Krol, G.Vorbrüggen, and H.Jäckle (2009).
A novel stem loop control element-dependent UGA read-through system without translational selenocysteine incorporation in Drosophila.
  FASEB J, 23, 107-113.  
19321438 V.B.Kurella, J.M.Richard, C.L.Parke, L.F.Lecour, H.D.Bellamy, and D.K.Worthylake (2009).
Crystal Structure of the GTPase-activating Protein-related Domain from IQGAP1.
  J Biol Chem, 284, 14857-14865.
PDB code: 3fay
18713003 L.Gremer, B.Gilsbach, M.R.Ahmadian, and A.Wittinghofer (2008).
Fluoride complexes of oncogenic Ras mutants to study the Ras-RasGap interaction.
  Biol Chem, 389, 1163-1171.  
17963711 X.Du, K.Ferguson, R.Gregory, and S.R.Sprang (2008).
A method to determine 18 O kinetic isotope effects in the hydrolysis of nucleotide triphosphates.
  Anal Biochem, 372, 213-221.  
16813595 A.B.Trovó-Marqui, and E.H.Tajara (2006).
Neurofibromin: a general outlook.
  Clin Genet, 70, 1.  
16479075 S.Y.Jeong, S.J.Park, and H.J.Kim (2006).
The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1.
  J Korean Med Sci, 21, 107-112.  
16380919 A.De Luca, I.Bottillo, A.Sarkozy, C.Carta, C.Neri, E.Bellacchio, A.Schirinzi, E.Conti, G.Zampino, A.Battaglia, S.Majore, M.M.Rinaldi, M.Carella, B.Marino, A.Pizzuti, M.C.Digilio, M.Tartaglia, and B.Dallapiccola (2005).
NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.
  Am J Hum Genet, 77, 1092-1101.  
15583390 F.Bonneau, I.D'Angelo, S.Welti, G.Stier, J.Ylänne, and K.Scheffzek (2004).
Expression, purification and preliminary crystallographic characterization of a novel segment from the neurofibromatosis type 1 protein.
  Acta Crystallogr D Biol Crystallogr, 60, 2364-2367.  
15075275 H.Chautard, M.Jacquet, F.Schoentgen, N.Bureaud, and H.Bénédetti (2004).
Tfs1p, a member of the PEBP family, inhibits the Ira2p but not the Ira1p Ras GTPase-activating protein in Saccharomyces cerevisiae.
  Eukaryot Cell, 3, 459-470.  
15210950 T.Hishida, Y.W.Han, S.Fujimoto, H.Iwasaki, and H.Shinagawa (2004).
Direct evidence that a conserved arginine in RuvB AAA+ ATPase acts as an allosteric effector for the ATPase activity of the adjacent subunit in a hexamer.
  Proc Natl Acad Sci U S A, 101, 9573-9577.  
12618308 A.Bernards (2003).
GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila.
  Biochim Biophys Acta, 1603, 47-82.  
12730209 S.Yunoue, H.Tokuo, K.Fukunaga, L.Feng, T.Ozawa, T.Nishi, A.Kikuchi, S.Hattori, J.Kuratsu, H.Saya, and N.Araki (2003).
Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras.
  J Biol Chem, 278, 26958-26969.  
14502561 T.Corral, M.Jiménez, I.Hernández-Muñoz, I.Pérez de Castro, and A.Pellicer (2003).
NF1 modulates the effects of Ras oncogenes: evidence of other NF1 function besides its GAP activity.
  J Cell Physiol, 197, 214-224.  
11861682 P.Nokelainen, and J.Flint (2002).
Genetic effects on human cognition: lessons from the study of mental retardation syndromes.
  J Neurol Neurosurg Psychiatry, 72, 287-296.  
11960693 S.Donovan, K.M.Shannon, and G.Bollag (2002).
GTPase activating proteins: critical regulators of intracellular signaling.
  Biochim Biophys Acta, 1602, 23-45.  
11748613 K.C.Chang, and N.N.Chuang (2001).
GTPase stimulation in shrimp Ras(Q(61)K) with geranylgeranyl pyrophosphate but not mammalian GAP.
  J Exp Zool, 290, 642-651.  
11707393 Y.H.Song, A.Marx, J.Müller, G.Woehlke, M.Schliwa, A.Krebs, A.Hoenger, and E.Mandelkow (2001).
Structure of a fast kinesin: implications for ATPase mechanism and interactions with microtubules.
  EMBO J, 20, 6213-6225.
PDB code: 1goj
11013213 A.Rak, R.Fedorov, K.Alexandrov, S.Albert, R.S.Goody, D.Gallwitz, and A.J.Scheidig (2000).
Crystal structure of the GAP domain of Gyp1p: first insights into interaction with Ypt/Rab proteins.
  EMBO J, 19, 5105-5113.
PDB code: 1fkm
11050620 G.S.Fisch (2000).
Mechanisms, models, and mental retardation.
  Am J Med Genet, 94, 372-375.  
10712197 R.Fahsold, S.Hoffmeyer, C.Mischung, C.Gille, C.Ehlers, N.Kücükceylan, M.Abdel-Nour, A.Gewies, H.Peters, D.Kaufmann, A.Buske, S.Tinschert, and P.Nürnberg (2000).
Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain.
  Am J Hum Genet, 66, 790-818.  
  10469432 B.Weiss, G.Bollag, and K.Shannon (1999).
Hyperactive Ras as a therapeutic target in neurofibromatosis type 1.
  Am J Med Genet, 89, 14-22.  
10469438 D.Viskochil (1999).
Neurofibromatosis 1
  Am J Med Genet, 89, V.  
10102276 J.Goldberg (1999).
Structural and functional analysis of the ARF1-ARFGAP complex reveals a role for coatomer in GTP hydrolysis.
  Cell, 96, 893-902.  
10489445 K.Longenecker, P.Read, U.Derewenda, Z.Dauter, X.Liu, S.Garrard, L.Walker, A.V.Somlyo, R.K.Nakamoto, A.P.Somlyo, and Z.S.Derewenda (1999).
How RhoGDI binds Rho.
  Acta Crystallogr D Biol Crystallogr, 55, 1503-1515.
PDB code: 1cc0
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.