| Structural highlights
Disease
[PEN2_HUMAN] Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. [NICA_HUMAN] Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. [PSN1_HUMAN] Defects in PSEN1 are a cause of Alzheimer disease type 3 (AD3) [MIM:607822]. AD3 is a familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [:][28] [29] [30] [31] [32] Defects in PSEN1 are a cause of frontotemporal dementia (FTD) [MIM:600274]. Defects in PSEN1 are the cause of cardiomyopathy dilated type 1U (CMD1U) [MIM:613694]. It is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[33] Defects in PSEN1 are the cause of familial acne inversa type 3 (ACNINV3) [MIM:613737]. A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty.[34]
Function
[PEN2_HUMAN] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Probably represents the last step of maturation of gamma-secretase, facilitating endoproteolysis of presenilin and conferring gamma-secretase activity.[35] [36] [NICA_HUMAN] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex. [APH1A_HUMAN] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex.[37] [38] [39] [PSN1_HUMAN] Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx, cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling. May also play a role in hematopoiesis.[40] [41] [42] [43] [44] [45] [46] [47]
Publication Abstract from PubMed
Human gamma-Secretase is an intra-membrane protease that cleaves many substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein lead to Alzheimer's disease. Our previous cryo-EM structure of gamma-secretase revealed considerable disorder in its catalytic subunit presenilin. Here, we describe an image classification procedure that characterizes molecular plasticity at the secondary structure level, and apply this method to identify three distinct conformations in our previous sample. In one of these conformations, an additional transmembrane helix is visible that cannot be attributed to known components of gamma-secretase. In addition, we present a gamma-secretase structure in complex with the dipeptidic inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). Our results reveal how conformational mobility in the second and sixth transmembrane helices of presenilin is greatly reduced upon binding of DAPT or the additional helix, and form the basis for a new model of how substrate enters the transmembrane domain.
Sampling the conformational space of the catalytic subunit of human gamma-secretase.,Bai XC, Rajendra E, Yang G, Shi Y, Scheres SH Elife. 2015 Dec 1;4. pii: e11182. doi: 10.7554/eLife.11182. PMID:26623517[48]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nielsen AL, Holm IE, Johansen M, Bonven B, Jorgensen P, Jorgensen AL. A new splice variant of glial fibrillary acidic protein, GFAP epsilon, interacts with the presenilin proteins. J Biol Chem. 2002 Aug 16;277(33):29983-91. Epub 2002 Jun 10. PMID:12058025 doi:10.1074/jbc.M112121200
- ↑ Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PMID:7596406 doi:http://dx.doi.org/10.1038/375754a0
- ↑ Cruts M, Backhovens H, Wang SY, Van Gassen G, Theuns J, De Jonghe CD, Wehnert A, De Voecht J, De Winter G, Cras P, et al.. Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PMID:8634711
- ↑ Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S, et al.. Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PMID:8634712
- ↑ Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al.. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PMID:7651536 doi:http://dx.doi.org/10.1038/376775a0
- ↑ . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Alzheimer's Disease Collaborative Group. Nat Genet. 1995 Oct;11(2):219-22. PMID:7550356 doi:http://dx.doi.org/10.1038/ng1095-219
- ↑ Kamino K, Sato S, Sakaki Y, Yoshiiwa A, Nishiwaki Y, Takeda M, Tanabe H, Nishimura T, Ii K, St George-Hyslop PH, Miki T, Ogihara T. Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996 Apr 26;208(3):195-8. PMID:8733303
- ↑ Crook R, Ellis R, Shanks M, Thal LJ, Perez-Tur J, Baker M, Hutton M, Haltia T, Hardy J, Galasko D. Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation. Ann Neurol. 1997 Jul;42(1):124-8. PMID:9225696 doi:10.1002/ana.410420121
- ↑ Lendon CL, Martinez A, Behrens IM, Kosik KS, Madrigal L, Norton J, Neuman R, Myers A, Busfield F, Wragg M, Arcos M, Arango Viana JC, Ossa J, Ruiz A, Goate AM, Lopera F. E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Hum Mutat. 1997;10(3):186-95. PMID:9298817 doi:<186::AID-HUMU2>3.0.CO;2-H 10.1002/(SICI)1098-1004(1997)10:3<186::AID-HUMU2>3.0.CO;2-H
- ↑ Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PMID:9172170
- ↑ Ramirez-Duenas MG, Rogaeva EA, Leal CA, Lin C, Ramirez-Casillas GA, Hernandez-Romo JA, St George-Hyslop PH, Cantu JM. A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with early onset Alzheimer disease. Ann Genet. 1998;41(3):149-53. PMID:9833068
- ↑ Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PMID:9384602
- ↑ Poorkaj P, Sharma V, Anderson L, Nemens E, Alonso ME, Orr H, White J, Heston L, Bird TD, Schellenberg GD. Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PMID:9521423 doi:<216::AID-HUMU6>3.0.CO;2-F 10.1002/(SICI)1098-1004(1998)11:3<216::AID-HUMU6>3.0.CO;2-F
- ↑ Besancon R, Lorenzi A, Cruts M, Radawiec S, Sturtz F, Broussolle E, Chazot G, van Broeckhoven C, Chamba G, Vandenberghe A. Missense mutation in exon 11 (Codon 378) of the presenilin-1 gene in a French family with early-onset Alzheimer's disease and transmission study by mismatch enhanced allele specific amplification. Mutations in brief no. 141. Online. besancon@rockefeller1.univ.lyon1.fr. Hum Mutat. 1998;11(6):481. PMID:10200054 doi:<481::AID-HUMU12>3.0.CO;2-Q 10.1002/(SICI)1098-1004(1998)11:6<481::AID-HUMU12>3.0.CO;2-Q
- ↑ Dumanchin C, Brice A, Campion D, Hannequin D, Martin C, Moreau V, Agid Y, Martinez M, Clerget-Darpoux F, Frebourg T. De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group. J Med Genet. 1998 Aug;35(8):672-3. PMID:9719376
- ↑ Wisniewski T, Dowjat WK, Buxbaum JD, Khorkova O, Efthimiopoulos S, Kulczycki J, Lojkowska W, Wegiel J, Wisniewski HM, Frangione B. A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years. Neuroreport. 1998 Jan 26;9(2):217-21. PMID:9507958
- ↑ Taddei K, Kwok JB, Kril JJ, Halliday GM, Creasey H, Hallupp M, Fisher C, Brooks WS, Chung C, Andrews C, Masters CL, Schofield PR, Martins RN. Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport. 1998 Oct 5;9(14):3335-9. PMID:9831473
- ↑ Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PMID:10441572 doi:S0002-9297(07)62317-9
- ↑ Palmer MS, Beck JA, Campbell TA, Humphries CB, Roques PK, Fox NC, Harvey R, Rossor MN, Collinge J. Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online. Hum Mutat. 1999;13(3):256. PMID:10090481 doi:<256::AID-HUMU12>3.0.CO;2-M 10.1002/(SICI)1098-1004(1999)13:3<256::AID-HUMU12>3.0.CO;2-M
- ↑ Sugiyama N, Suzuki K, Matsumura T, Kawanishi C, Onishi H, Yamada Y, Iseki E, Kosaka K. A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease. Mutation in brief no. 254. Online. Hum Mutat. 1999;14(1):90. PMID:10447269 doi:<90::AID-HUMU19>3.0.CO;2-S 10.1002/(SICI)1098-1004(1999)14:1<90::AID-HUMU19>3.0.CO;2-S
- ↑ Aldudo J, Bullido MJ, Valdivieso F. DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations. Hum Mutat. 1999;14(5):433-9. PMID:10533070 doi:<433::AID-HUMU10>3.0.CO;2-K 10.1002/(SICI)1098-1004(199911)14:5<433::AID-HUMU10>3.0.CO;2-K
- ↑ Ezquerra M, Carnero C, Blesa R, Gelpi JL, Ballesta F, Oliva R. A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and myoclonic seizures. Neurology. 1999 Feb;52(3):566-70. PMID:10025789
- ↑ Smith MJ, Gardner RJ, Knight MA, Forrest SM, Beyreuther K, Storey E, McLean CA, Cotton RG, Cappal R, Masters CL. Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene. Neuroreport. 1999 Feb 25;10(3):503-7. PMID:10208579
- ↑ Romero I, Jorgensen P, Bolwig G, Fraser PE, Rogaeva E, Mann D, Havsager AM, Jorgensen AL. A presenilin-1 Thr116Asn substitution in a family with early-onset Alzheimer's disease. Neuroreport. 1999 Aug 2;10(11):2255-60. PMID:10439444
- ↑ Finckh U, Muller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000 Jan;66(1):110-7. PMID:10631141 doi:S0002-9297(07)62237-X
- ↑ Yasuda M, Maeda S, Kawamata T, Tamaoka A, Yamamoto Y, Kuroda S, Maeda K, Tanaka C. Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry. 2000 Feb;68(2):220-3. PMID:10644793
- ↑ Lewis PA, Perez-Tur J, Golde TE, Hardy J. The presenilin 1 C92S mutation increases abeta 42 production. Biochem Biophys Res Commun. 2000 Oct 14;277(1):261-3. PMID:11027672 doi:10.1006/bbrc.2000.3646
- ↑ Athan ES, Williamson J, Ciappa A, Santana V, Romas SN, Lee JH, Rondon H, Lantigua RA, Medrano M, Torres M, Arawaka S, Rogaeva E, Song YQ, Sato C, Kawarai T, Fafel KC, Boss MA, Seltzer WK, Stern Y, St George-Hyslop P, Tycko B, Mayeux R. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA. 2001 Nov 14;286(18):2257-63. PMID:11710891
- ↑ Matsubara-Tsutsui M, Yasuda M, Yamagata H, Nomura T, Taguchi K, Kohara K, Miyoshi K, Miki T. Molecular evidence of presenilin 1 mutation in familial early onset dementia. Am J Med Genet. 2002 Apr 8;114(3):292-8. PMID:11920851
- ↑ Moehlmann T, Winkler E, Xia X, Edbauer D, Murrell J, Capell A, Kaether C, Zheng H, Ghetti B, Haass C, Steiner H. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8025-30. Epub 2002 Jun 4. PMID:12048239 doi:10.1073/pnas.112686799
- ↑ Bertoli Avella AM, Marcheco Teruel B, Llibre Rodriguez JJ, Gomez Viera N, Borrajero Martinez I, Severijnen EA, Joosse M, van Duijn CM, Heredero Baute L, Heutink P. A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease. Neurogenetics. 2002 Oct;4(2):97-104. PMID:12484344
- ↑ Kwok JB, Halliday GM, Brooks WS, Dolios G, Laudon H, Murayama O, Hallupp M, Badenhop RF, Vickers J, Wang R, Naslund J, Takashima A, Gandy SE, Schofield PR. Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy. J Biol Chem. 2003 Feb 28;278(9):6748-54. Epub 2002 Dec 19. PMID:12493737 doi:10.1074/jbc.M211827200
- ↑ Li D, Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Partain J, Nixon RR, Allen CN, Irwin RP, Jakobs PM, Litt M, Hershberger RE. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24. PMID:17186461 doi:10.1086/509900
- ↑ Wang B, Yang W, Wen W, Sun J, Su B, Liu B, Ma D, Lv D, Wen Y, Qu T, Chen M, Sun M, Shen Y, Zhang X. Gamma-secretase gene mutations in familial acne inversa. Science. 2010 Nov 19;330(6007):1065. doi: 10.1126/science.1196284. Epub 2010 Oct , 7. PMID:20929727 doi:10.1126/science.1196284
- ↑ Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Thinakaran G, Kim TW, Yu G, Xu H. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem. 2003 Mar 7;278(10):7850-4. Epub 2003 Jan 8. PMID:12522139 doi:http://dx.doi.org/10.1074/jbc.C200648200
- ↑ Marlow L, Canet RM, Haugabook SJ, Hardy JA, Lahiri DK, Sambamurti K. APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity. Biochem Biophys Res Commun. 2003 Jun 6;305(3):502-9. PMID:12763021
- ↑ Lee SF, Shah S, Li H, Yu C, Han W, Yu G. Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J Biol Chem. 2002 Nov 22;277(47):45013-9. Epub 2002 Sep 23. PMID:12297508 doi:http://dx.doi.org/10.1074/jbc.M208164200
- ↑ Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Thinakaran G, Kim TW, Yu G, Xu H. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem. 2003 Mar 7;278(10):7850-4. Epub 2003 Jan 8. PMID:12522139 doi:http://dx.doi.org/10.1074/jbc.C200648200
- ↑ Marlow L, Canet RM, Haugabook SJ, Hardy JA, Lahiri DK, Sambamurti K. APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity. Biochem Biophys Res Commun. 2003 Jun 6;305(3):502-9. PMID:12763021
- ↑ Steiner H, Romig H, Pesold B, Philipp U, Baader M, Citron M, Loetscher H, Jacobsen H, Haass C. Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis. Biochemistry. 1999 Nov 2;38(44):14600-5. PMID:10545183
- ↑ Ray WJ, Yao M, Mumm J, Schroeter EH, Saftig P, Wolfe M, Selkoe DJ, Kopan R, Goate AM. Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J Biol Chem. 1999 Dec 17;274(51):36801-7. PMID:10593990
- ↑ Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999 Apr 8;398(6727):513-7. PMID:10206644 doi:10.1038/19077
- ↑ Berezovska O, Jack C, McLean P, Aster JC, Hicks C, Xia W, Wolfe MS, Kimberly WT, Weinmaster G, Selkoe DJ, Hyman BT. Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling. J Neurochem. 2000 Aug;75(2):583-93. PMID:10899933
- ↑ Kulic L, Walter J, Multhaup G, Teplow DB, Baumeister R, Romig H, Capell A, Steiner H, Haass C. Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5913-8. PMID:10811883 doi:10.1073/pnas.100049897
- ↑ Baki L, Marambaud P, Efthimiopoulos S, Georgakopoulos A, Wen P, Cui W, Shioi J, Koo E, Ozawa M, Friedrich VL Jr, Robakis NK. Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2381-6. PMID:11226248 doi:10.1073/pnas.041603398
- ↑ Wrigley JD, Nunn EJ, Nyabi O, Clarke EE, Hunt P, Nadin A, De Strooper B, Shearman MS, Beher D. Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding. J Neurochem. 2004 Sep;90(6):1312-20. PMID:15341515 doi:10.1111/j.1471-4159.2004.02596.x
- ↑ Wang J, Beher D, Nyborg AC, Shearman MS, Golde TE, Goate A. C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation. J Neurochem. 2006 Jan;96(1):218-27. Epub 2005 Nov 23. PMID:16305624 doi:JNC3548
- ↑ Bai XC, Rajendra E, Yang G, Shi Y, Scheres SH. Sampling the conformational space of the catalytic subunit of human gamma-secretase. Elife. 2015 Dec 1;4. pii: e11182. doi: 10.7554/eLife.11182. PMID:26623517 doi:http://dx.doi.org/10.7554/eLife.11182
|
