PDBsum entry 1mwp

Go to PDB code: 
protein links
Sugar binding protein PDB id
Protein chain
96 a.a. *
Waters ×120
* Residue conservation analysis
PDB id:
Name: Sugar binding protein
Title: N-terminal domain of the amyloid precursor protein
Structure: Amyloid a4 protein. Chain: a. Fragment: heparin binding domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cellular_location: cell surface. Expressed in: pichia pastoris. Expression_system_taxid: 4922
1.80Å     R-factor:   0.203     R-free:   0.242
Authors: J.Rossjohn,R.Cappai,S.C.Feil,A.Henry,W.J.Mckinstry, D.Galatis,L.Hesse,G.Multhaup,K.Beyreuther,C.L.Masters, M.W.Parker
Key ref:
J.Rossjohn et al. (1999). Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein. Nat Struct Biol, 6, 327-331. PubMed id: 10201399 DOI: 10.1038/7562
09-Mar-99     Release date:   15-Mar-00    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P05067  (A4_HUMAN) -  Amyloid beta A4 protein
770 a.a.
96 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     nervous system development   1 term 
  Biochemical function     heparin binding     1 term  


DOI no: 10.1038/7562 Nat Struct Biol 6:327-331 (1999)
PubMed id: 10201399  
Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein.
J.Rossjohn, R.Cappai, S.C.Feil, A.Henry, W.J.McKinstry, D.Galatis, L.Hesse, G.Multhaup, K.Beyreuther, C.L.Masters, M.W.Parker.
Amyloid precursor protein (APP) plays a central role in Alzheimer disease. A proteolytic-breakdown product of APP, called beta-amyloid, is a major component of the diffuse and fibrillar deposits found in Alzheimer diseased brains. The normal physiological role of APP remains largely unknown despite much work. A knowledge of its function will not only provide insights into the genesis of the disease but may also prove vital in the development of an effective therapy. Here we describe the 1.8 A resolution crystal structure of the N-terminal, heparin-binding domain of APP (residues 28-123), which is responsible, among other things, for stimulation of neurite outgrowth. The structure reveals a highly charged basic surface that may interact with glycosaminoglycans in the brain and an abutting hydrophobic surface that is proposed to play an important functional role such as dimerization or ligand binding. Structural similarities with cysteine-rich growth factors, taken together with its known growth-promoting properties, suggests the APP N-terminal domain could function as a growth factor in vivo.
  Selected figure(s)  
Figure 1.
Figure 1. Structure of the APP N-terminal domain. a, A ribbon diagram indicating the location of secondary structure. Sheet A is colored blue, sheet B is in orange and sheet C is shown in brown. The disulfide bridges are shown in ball-and-stick, and the tip of the -hairpin loop is indicated. This figure was drawn with MOLSCRIPT^29. b, A stereo diagram of a C trace of the structure, shown in the same orientation as in (a), with every 20^th residue labeled. c, An orthogonal view drawn as a CPK representation. Basic residues are in blue, acidic residues in red, polar residues in pink and hydrophobic residues in green. The locations of key regions are highlighted. This figure was drawn with GRASP^30. d, Stereo 2F[o] - F[c] electron density map (blue), calculated using the final model, at 1.8 Å resolution. The map is contoured at 1 , with the final model overlaid upon it. The region shown corresponds to part of the hydrophobic core of the protein.
Figure 3.
Figure 3. Electrostatic surface representations^30 of APP family members. Blue indicates electropositive potential (> 10 kT) and red indicates electronegative potential (< -10 kT).
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (1999, 6, 327-331) copyright 1999.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21170735 A.Castorina, G.M.Leggio, S.Giunta, G.Magro, G.Scapagnini, F.Drago, and V.D'Agata (2011).
Neurofibromin and amyloid precursor protein expression in dopamine d3 receptor knock-out mice brains.
  Neurochem Res, 36, 426-434.  
21337622 S.Y.Ponomarev, and J.Audie (2011).
Computational prediction and analysis of the DR6-NAPP interaction.
  Proteins, 79, 1376-1395.  
20731541 D.W.Klaver, M.C.Wilce, H.Cui, A.C.Hung, R.Gasperini, L.Foa, and D.H.Small (2010).
Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions.
  Biol Chem, 391, 849-859.  
19906646 J.T.Hoopes, X.Liu, X.Xu, B.Demeler, E.Folta-Stogniew, C.Li, and Y.Ha (2010).
Structural characterization of the E2 domain of APL-1, a Caenorhabditis elegans homolog of human amyloid precursor protein, and its heparin binding site.
  J Biol Chem, 285, 2165-2173.
PDB codes: 3k66 3k6b
19759550 M.G.Botelho, X.Wang, D.J.Arndt-Jovin, D.Becker, and T.M.Jovin (2010).
Induction of terminal differentiation in melanoma cells on downregulation of beta-amyloid precursor protein.
  J Invest Dermatol, 130, 1400-1410.  
20809979 M.S.Fustiñana, P.Ariel, N.Federman, R.Freudenthal, and A.Romano (2010).
Characterization of the beta amyloid precursor protein-like gene in the central nervous system of the crab Chasmagnathus. Expression during memory consolidation.
  BMC Neurosci, 11, 109.  
19058878 S.A.Austin, and C.K.Combs (2010).
Amyloid precursor protein mediates monocyte adhesion in AD tissue and apoE(-)/(-) mice.
  Neurobiol Aging, 31, 1854-1866.  
20212142 S.O.Dahms, S.Hoefgen, D.Roeser, B.Schlott, K.H.Gührs, and M.E.Than (2010).
Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein.
  Proc Natl Acad Sci U S A, 107, 5381-5386.
PDB code: 3ktm
20458444 X.Fan, Y.Liu, J.Jiang, Z.Ma, H.Wu, T.Liu, M.Liu, X.Li, and H.Tang (2010).
miR-20a promotes proliferation and invasion by targeting APP in human ovarian cancer cells.
  Acta Biochim Biophys Sin (Shanghai), 42, 318-324.  
20309664 Y.D.Kwak, E.Dantuma, S.Merchant, S.Bushnev, and K.Sugaya (2010).
Amyloid-β precursor protein induces glial differentiation of neural progenitor cells by activation of the IL-6/gp130 signaling pathway.
  Neurotox Res, 18, 328-338.  
19336403 M.Gralle, M.G.Botelho, and F.S.Wouters (2009).
Neuroprotective secreted amyloid precursor protein acts by disrupting amyloid precursor protein dimers.
  J Biol Chem, 284, 15016-15025.  
19542221 P.Porayette, M.J.Gallego, M.M.Kaltcheva, R.L.Bowen, S.Vadakkadath Meethal, and C.S.Atwood (2009).
Differential processing of amyloid-beta precursor protein directs human embryonic stem cell proliferation and differentiation into neuronal precursor cells.
  J Biol Chem, 284, 23806-23817.  
19923279 S.A.Austin, M.A.Sens, and C.K.Combs (2009).
Amyloid precursor protein mediates a tyrosine kinase-dependent activation response in endothelial cells.
  J Neurosci, 29, 14451-14462.  
18702528 A.J.Beel, C.K.Mobley, H.J.Kim, F.Tian, A.Hadziselimovic, B.Jap, J.H.Prestegard, and C.R.Sanders (2008).
Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor?
  Biochemistry, 47, 9428-9446.  
18182389 D.Kaden, L.M.Munter, M.Joshi, C.Treiber, C.Weise, T.Bethge, P.Voigt, M.Schaefer, M.Beyermann, B.Reif, and G.Multhaup (2008).
Homophilic interactions of the amyloid precursor protein (APP) ectodomain are regulated by the loop region and affect beta-secretase cleavage of APP.
  J Biol Chem, 283, 7271-7279.  
18030462 G.K.Kong, L.A.Miles, G.A.Crespi, C.J.Morton, H.L.Ng, K.J.Barnham, W.J.McKinstry, R.Cappai, and M.W.Parker (2008).
Copper binding to the Alzheimer's disease amyloid precursor protein.
  Eur Biophys J, 37, 269-279.  
18650430 G.Thinakaran, and E.H.Koo (2008).
Amyloid precursor protein trafficking, processing, and function.
  J Biol Chem, 283, 29615-29619.  
18573216 T.L.Young-Pearse, A.C.Chen, R.Chang, C.Marquez, and D.J.Selkoe (2008).
Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1.
  Neural Develop, 3, 15.  
18607649 Y.Mantri, M.Fioroni, and M.H.Baik (2008).
Computational study of the binding of Cu(II) to Alzheimer's amyloid-beta peptide: Do Abeta42 and Abeta40 bind copper in identical fashion?
  J Biol Inorg Chem, 13, 1197-1204.  
  17909280 G.K.Kong, J.J.Adams, R.Cappai, and M.W.Parker (2007).
Structure of Alzheimer's disease amyloid precursor protein copper-binding domain at atomic resolution.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 819-824.
PDB code: 2fma
17332749 L.M.Munter, P.Voigt, A.Harmeier, D.Kaden, K.E.Gottschalk, C.Weise, R.Pipkorn, M.Schaefer, D.Langosch, and G.Multhaup (2007).
GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42.
  EMBO J, 26, 1702-1712.  
17428603 M.Gralle, and S.T.Ferreira (2007).
Structure and functions of the human amyloid precursor protein: the whole is more than the sum of its parts.
  Prog Neurobiol, 82, 11-32.  
16805778 C.L.Masters, R.Cappai, K.J.Barnham, and V.L.Villemagne (2006).
Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics.
  J Neurochem, 97, 1700-1725.  
16539666 C.M.Sondag, and C.K.Combs (2006).
Amyloid precursor protein cross-linking stimulates beta amyloid production and pro-inflammatory cytokine release in monocytic lineage cells.
  J Neurochem, 97, 449-461.  
16930452 H.Zheng, and E.H.Koo (2006).
The amyloid precursor protein: beyond amyloid.
  Mol Neurodegener, 1, 5.  
16846374 W.Phillips, A.W.Michell, and R.A.Barker (2006).
Neurogenesis in diseases of the central nervous system.
  Stem Cells Dev, 15, 359-379.  
16846375 Y.D.Kwak, C.L.Brannen, T.Qu, H.M.Kim, X.Dong, P.Soba, A.Majumdar, A.Kaplan, K.Beyreuther, and K.Sugaya (2006).
Amyloid precursor protein regulates differentiation of human neural stem cells.
  Stem Cells Dev, 15, 381-389.  
15576561 A.T.Alexandrescu (2005).
Amyloid accomplices and enforcers.
  Protein Sci, 14, 1.  
16252002 C.Reinhard, S.S.Hébert, and B.De Strooper (2005).
The amyloid-beta precursor protein: integrating structure with biological function.
  EMBO J, 24, 3996-4006.  
  16508101 G.K.Kong, D.Galatis, K.J.Barnham, G.Polekhina, J.J.Adams, C.L.Masters, R.Cappai, M.W.Parker, and W.J.McKinstry (2005).
Crystallization and preliminary crystallographic studies of the copper-binding domain of the amyloid precursor protein of Alzheimer's disease.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 93-95.  
15667924 L.Conti, and E.Cattaneo (2005).
Controlling neural stem cell division within the adult subventricular zone: an APPealing job.
  Trends Neurosci, 28, 57-59.  
15677459 R.Cappai, F.Cheng, G.D.Ciccotosto, B.E.Needham, C.L.Masters, G.Multhaup, L.A.Fransson, and K.Mani (2005).
The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo.
  J Biol Chem, 280, 13913-13920.  
15760906 R.H.Law, J.A.Irving, A.M.Buckle, K.Ruzyla, M.Buzza, T.A.Bashtannyk-Puhalovich, T.C.Beddoe, K.Nguyen, D.M.Worrall, S.P.Bottomley, P.I.Bird, J.Rossjohn, and J.C.Whisstock (2005).
The high resolution crystal structure of the human tumor suppressor maspin reveals a novel conformational switch in the G-helix.
  J Biol Chem, 280, 22356-22364.
PDB codes: 1wz9 1xu8
15333934 C.Keil, R.Huber, W.Bode, and M.E.Than (2004).
Cloning, expression, crystallization and initial crystallographic analysis of the C-terminal domain of the amyloid precursor protein APP.
  Acta Crystallogr D Biol Crystallogr, 60, 1614-1617.  
14732706 C.M.Sondag, and C.K.Combs (2004).
Amyloid precursor protein mediates proinflammatory activation of monocytic lineage cells.
  J Biol Chem, 279, 14456-14463.  
15465814 C.Treiber, A.Simons, M.Strauss, M.Hafner, R.Cappai, T.A.Bayer, and G.Multhaup (2004).
Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer's disease.
  J Biol Chem, 279, 51958-51964.  
15272266 E.Bossy-Wetzel, R.Schwarzenbacher, and S.A.Lipton (2004).
Molecular pathways to neurodegeneration.
  Nat Med, 10, S2-S9.  
15450250 N.Landman, and T.W.Kim (2004).
Got RIP? Presenilin-dependent intramembrane proteolysis in growth factor receptor signaling.
  Cytokine Growth Factor Rev, 15, 337-351.  
12611883 K.J.Barnham, W.J.McKinstry, G.Multhaup, D.Galatis, C.J.Morton, C.C.Curtain, N.A.Williamson, A.R.White, M.G.Hinds, R.S.Norton, K.Beyreuther, C.L.Masters, M.W.Parker, and R.Cappai (2003).
Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis.
  J Biol Chem, 278, 17401-17407.
PDB code: 1owt
12859342 K.Tang, C.Wang, C.Shen, S.Sheng, R.Ravid, and N.Jing (2003).
Identification of a novel alternative splicing isoform of human amyloid precursor protein gene, APP639.
  Eur J Neurosci, 18, 102-108.  
12796495 M.G.Botelho, M.Gralle, C.L.Oliveira, I.Torriani, and S.T.Ferreira (2003).
Folding and stability of the extracellular domain of the human amyloid precursor protein.
  J Biol Chem, 278, 34259-34267.  
12496118 M.Gralle, M.M.Botelho, Oliveira, I.Torriani, and S.T.Ferreira (2002).
Solution studies and structural model of the extracellular domain of the human amyloid precursor protein.
  Biophys J, 83, 3513-3524.  
12142279 W.Annaert, and B.De Strooper (2002).
A cell biological perspective on Alzheimer's disease.
  Annu Rev Cell Dev Biol, 18, 25-51.  
12107175 W.E.Van Nostrand, J.P.Melchor, D.M.Keane, S.M.Saporito-Irwin, G.Romanov, J.Davis, and F.Xu (2002).
Localization of a fibrillar amyloid beta-protein binding domain on its precursor.
  J Biol Chem, 277, 36392-36398.  
11309494 E.Kojro, G.Gimpl, S.Lammich, W.Marz, and F.Fahrenholz (2001).
Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM 10.
  Proc Natl Acad Sci U S A, 98, 5815-5820.  
11238726 I.Ohsawa, C.Takamura, and S.Kohsaka (2001).
Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein and modulates its physiological function.
  J Neurochem, 76, 1411-1420.  
11277983 J.W.Kusiak, L.L.Lee, and B.Zhao (2001).
Expression of mutant amyloid precursor proteins decreases adhesion and delays differentiation of Hep-1 cells.
  Brain Res, 896, 146-152.  
10734132 J.P.Melchor, and W.E.Van Nostrand (2000).
Fibrillar amyloid beta-protein mediates the pathologic accumulation of its secreted precursor in human cerebrovascular smooth muscle cells.
  J Biol Chem, 275, 9782-9791.  
10858290 M.R.Wagner, D.M.Keane, J.P.Melchor, K.R.Auspaker, and W.E.Van Nostrand (2000).
Fibrillar amyloid beta-protein binds protease nexin-2/amyloid beta-protein precursor: stimulation of its inhibition of coagulation factor XIa.
  Biochemistry, 39, 7420-7427.  
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.