Gefei Chen

Gefei Chen

Assistant professor

Email:
gefei.chen@ki.se
Organisation:

Research description

Research group

Surveillance by molecular chaperones may decline, and proteins misfold and self-assemble into amorphous aggregates as well as fibrillar amyloid which are linked to cureless human diseases. Our research aims to understand how molecular chaperones interfere with different types of protein aggregation and alleviate relevant toxicities, and augment specific chaperone capacity for novel treatment developments, in particular against cancer and neurodegenerative diseases. On the other side, non-pathological amyloid is supposed to be shared by spider silk, one of the toughest biomaterials. Currently, our understanding of amyloid-like formation during spider silk assembly process and underlying mechanisms are largely missing.

Selected publications

(*corresponding author, #equal contribution) 

[40] Qi X, Wang Y, Yu H.; Liu R, Leppert A, Zheng Z, Zhong X, Jin Z, Wang H, Li X, Wang X, Landreh M, A. Morozova-Roche L, Johansson J, Xiong S, Iashchishyn I, Chen G*. Spider Silk Protein Forms Amyloid-Like Nanofibrils through a Non-Nucleation-Dependent Polymerization Mechanism. Small, 2023, 2304031.

[39] Medina-Vera D, Zhao H, Bereczki E, Rosell-Valle C, Shimozawa M, Chen G, de Fonseca F.R, Nilsson P, Tambaro S. The Expression of the Endocannabinoid Receptors CB2 and GPR55 is Highly Increased during the Progression of Alzheimer’s Disease in AppNL-G-F Knock-In Mice. Biology, 2023, 12, 805.

[38] Chen G*, Leppert A, Poska H, Nilsson H, Carlos A, Zhong X, Koeck P, Jegerschöld C, Abelein A, Hebert H, Johansson J. Short hydrophobic loop motifs in BRICHOS domains determine chaperone activity against amorphous protein aggregation but not against amyloid formation. Communications Biology, 2023, 6, 497.

[37] Leppert A, Chen G, Lama D, Sahin C, Railaite V, Shilkova O, Arndt T, Marklund E, Lane D, Rising A, Landreh M. Liquid-liquid phase separation primes spider silk proteins for fiber formation via a conditional sticker domain. Nano Letters, 2023, , 23, 12, 5836–5841.

[36] Leppert A, Poska H, Landreh M, Abelein A, Chen G, Johansson J. A new kid in the folding funnel: Molecular chaperone activities of the BRICHOS domain. Protein Science, 2023, e4645.

[35] Saluri M, Leppert A, Gese G, Sahin C, Lama D, Kaldmäe M, Chen G, Elofsson A, Allison T, Arsenian-Henriksson M, Johansson J, P. Lane D, Hällberg M, Landreh M. A "grappling hook" interaction connects self-assembly and chaperone activity of Nucleophosmin 1. PNAS Nexus, 2023, 2(2): pgac303.

[34] Andrade-Talavera Y#, Chen G#, Pansieri J#, Arroyo-García L. E, Toleikis Z, Smirnovas V, Johansson J, Morozova-Roche L, Fisahn A. S100A9 amyloid growth and S100A9 fibril-induced impairment of gamma oscillations in area CA3 of mouse hippocampus ex vivo is prevented by Bri2 BRICHOS. Progress in Neurobiology, Progress in Neurobiology, 2022, 219:102366.

[33] Chen G*, Andrade-Talavera Y, Zhong X, Hassan S, Biverstal H, Poska H, Abelein A, Leppert A, Kronqvist N, Rising A, Hebert H, Koeck P, Fisahn A, Johansson J. Ability of the BRICHOS domain to prevent neurotoxicity and fibril formation are dependent on a highly conserved Asp residue. RSC Chemical Biology, 2022, 3:1342-1358.

[32] Manchanda S, Galan-Acosta L, Abelein A, Tambaro S, Chen G, Nilsson P, Johansson J. Intravenous treatment with a molecular chaperone designed against amyloid-β toxicity improves features of Alzheimer disease pathology in mouse models. Molecular Therapy, 2022, S1525-0016(22)00498-1.

[31] Arndt T, Jaudzems K, Shilkova O, Francis J, Johansson M, Laity P, Sahin C, Chatterjee U, Kronqvist N, Barajas-Ledesma E, Kumar R, Chen G, Strömberg R, Abelein A, Langton M, Landreh M, Barth A, Holland C, Johansson J, Rising A. Spidroin N-terminal domain forms amyloid-like fibril based hydrogels and provides a protein immobilization platform. Nature Communications, 2022, 13(1):4695.

[30] Zhong X, Kumar R, Wang Y, Biverstal H, Jegerschöld C, Koeck P, Johansson J, Abelein A, Chen G*. Amyloid fibril formation of Arctic amyloid-β 1–42 peptide is efficiently inhibited by the BRICHOS domain. ACS Chemical Biology, 2022, 17(8):2201-2211.

[29] Tang X, Liu L, Miao Z, Zhang J, Cai X, Zhao B-Q, Chen G, Schultzberg M, Zhao Y, Wang X. Resolution of inflammation is disturbed in acute ischemic stroke with diabetes mellitus and rescued by resolvin D2 treatment. Free Radical Biology and Medicine, 2022, 188:194-205.

[28] Jiang R, Smailovic U, Haytural H, Tijms B, Li H, Haret R, Shevchenko G, Chen G, Abelein A, Gobom J, Frykman S, Sekiguchi M, Fujioka R, Watamura N, Sasaguri H, Nystrom S, Hammarstrom P, Saido T, Jelic V, Syvanen S, Zetterberg H, Winblad B; Bergquist J, Visser P, Nilsson P. Increased CSF-decorin predicts brain pathological changes driven by Alzheimer’s Aβ amyloidosis. Acta Neuropathologica Communications, 2022, 10(1):96.

[27] Leppert A, Chen G, Lianoudaki D, Williams C, Zhong X, Gilthorpe J, Landreh M, Johansson J. ATP-independent molecular chaperone activity generated under reducing conditions. Protein Science, 2022, 31(8): e4378.

[26] Kaldmäe M, Vosselman T, Zhong X, Lama D, Chen G, Saluri M, Kronqvis N, Siau J, Seng Ng A, Ghadessy F, Sabatier P, Vojtesek B, Sarr M, Sahin C, Österlund N, Ilag L, Väänänen V, Sedimbi S, Arsenian-Henriksson M, Zubarev R, Nilsson L, Koeck P, Rising A, Abelein A, Fritz N, Johansson J, Lane D, and Landreh M. A “spindle and thread”-mechanism unblocks p53 translation by modulating N-terminal disorder. Structure, 2022, 30(5):733-742.

[25] Oliveira D, Svensson J, Zhong X, Biverstål, Chen G*#, Karlström H*#. Molecular chaperone BRICHOS inhibits CADASIL-mutated NOTCH3 aggregation in vitro. Frontiers in Molecular Biosciences, 2022, 9:812808.

[24] Li X, Qi X, Cai Y, Sun Y, Wen R, Zhang R, Johansson J, Meng Q*, Chen G*. Customized flagelliform spidroins form spider silk-like fibers at pH 8.0 with outstanding tensile strength. ACS Biomaterials Science & Engineering, 2022, 8(1): 119-127.

[23] Rising A, Gherardi P, Chen G, Johansson J, Oskarsson M, Westermark G, Westermark P. AA amyloid in human food chain is a possible biohazard. Scientific Reports, 2021, 11:21069.

[22] Andrade-Talavera Y, Chen G, Kurudenkandy F, Johansson J, Fisahn A. Bri2 BRICHOS chaperone rescues impaired fast-spiking interneuron behavior and neuronal network dynamics in an AD mouse model in vitro. Neurobiology of Disease, 2021, 159:105514.

[21] Schmuck B, Chen G, Pelcman J, Kronkvist N, Rising A, Johansson J. Expression of the human molecular chaperone domain Bri2 BRICHOS on a gram per liter scale with an E. coli fed-batch culture. Microbial Cell Factories, 2021, 20(1):150.

[20] Zhao Q, Gong S, Jiang R, Li C, Chen G, Luo C, Qiu H, Liu J, Wang L, Zhang R. Echocardiographic prognosis relevance of attenuated right heart remodeling in idiopathic pulmonary arterial hypertension[J]. Frontiers in Cardiovascular Medicine, 2021, 8:650848.

[19] Andrade-Talavera Y, Balleza-Tapia H, Dolz-Gaiton P, Chen G, Johansson J, Fisahn A. Ablation of p75NTR-signaling strengthens gamma-theta rhythm interaction and counteracts Aβ-induced degradation of neuronal dynamics in mouse hippocampus in vitro[J]. Translational Psychiatry, 2021, 11:212.

[18] Tigro H, Kronqvist N, Abelein A, Galan-Acosta L, Chen G, Lyashkov A, Aon M.A, Ferrucci L, Shimmo R, Johansson J, Moaddel R. The synthesis and characterization of Bri2 BRICHOS coated magnetic particles and their application to Protein Fishing: Identification of novel binding proteins[J]. Journal of Pharmaceutical and Biomedical Analysis, 2021, 198:113996.

[17]    Cai H#, Chen G#, Yu H, Tang Y, Xiong S, Qi X. One-step heating strategy for efficient solubilization of recombinant spider silk protein from inclusion bodies[J]. BMC Biotechnology, 2020, 20(1):37. (#equal contributions)

[16]    Andrade-Talavera Y, Arroyo-García L, Chen G, Johansson J, Fisahn A. Modulation of Kv3.1/Kv3.2 promotes gamma oscillations by rescuing Aβ-induced desynchronization of fast-spiking interneuron firing in an AD mouse model[J]. The Journal of Physiology, 2020, 598(17):3711-3725.

[15]    Poska H, Leppert A, Tigro H, Zhong X, Kaldmäe M, Nilsson H, Hebert H, Chen G, Johansson J. Recombinant Bri3 BRICHOS domain is a bifunctional molecular chaperone[J]. Scientific Reports, 2020, 10(1): 9817.

[14]    Chen G, Andrade-Talavera Y, Tambaro S, Leppert A, Nilsson H, Zhong X, Landreh M, Nilsson P, Hebert H, Biverstål H, Fisahn A, Abelein A, Johansson J. Augmentation of Bri2 molecular chaperone activity against amyloid-β reduces neurotoxicity in mouse hippocampus in vitro[J]. Communications Biology, 2020, 3(1): 32.

[13]    Abelein A, Chen G, Kitoka K, Aleksis R, Oleskovs F, Sarr M, Landreh M, Pahnke J, Nordling K, Kronqvist N, Jaudzems K, Rising A, Johansson J, Biverstål H. High-yield Production of Amyloid-β Peptide Enabled by a Customized Spider Silk Domain[J]. Scientific Reports, 2020, 10(1):235.

[12]    Kaldmäe M, Leppert A, Chen G, Sarr M, Sahin C, Nordling K, Kronqvist N, Gonzalvo-Ulla M, Fritz N, Abelein A, Laίn S, Biverstål H, Jörnvall H, Lane DP, Rising A, Johansson J, Landreh M. High intracellular stability of the spidroin N-terminal domain in spite of abundant amyloidogenic segments revealed by in-cell hydrogen/deuterium exchange mass spectrometry[J]. The FEBS Journal, 2020, 287(13):2823-2833.

[11]    Leppert A, Chen G, Johansson J. BRICHOS: a chaperone with different activities depending on quaternary structure and cellular location?[J]. Amyloid, 2019, 26(sup1):152-153.

[10]    Tambaro S, Galan-Acosta L, Leppert A, Chen G, Biverstål H, Presto J, Nilsson P, Johansson J. Blood-brain and blood-cerebrospinal fluid passage of different BRICHOS molecular chaperone domains[J]. The Journal of Biological Chemistry, 2019, 294(8): 2606-2615.

[9]    Balleza-Tapia H, Crux S, Andrade-Talavera Y, Dolz-Gaiton P, Papadia D, Chen G, Johansson J, Fisahn A. TrpV1 receptor activation rescues neuronal function and network gamma oscillations from Aβ-induced impairment in mouse hippocampus in vitro[J]. eLife, 2018, 7: e37703.

[8]    Sarr M, Kronqvist N, Chen G, Aleksis R, Purhonen P, Hebert H, Jaudzems K, Rising A, Johansson J. A spidroin-derived solubility tag enables controlled aggregation of a designed amyloid protein[J]. The FEBS Journal, 2018, 285(10): 1873-1885.

[7]    Chen G, Abelein A, Nilsson H, Leppert A, Andrade-Talavera Y, Tambaro S, Hemmingsson L, Roshan F, Landreh M, Biverstål H, Koeck P, Presto J, Hebert H, Fisahn A, Johansson J. Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state[J]. Nature Communications, 2017, 8: 2081.

[6]    Poska H, Haslbeck M, Kurudenkandy FR, Hermansson E, Chen G, Kostallas G, Abelein A, Biverstål H, Crux S, Fisahn A, Presto J, Johansson J. Dementia related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits Abeta42 toxicity in Drosophila[J]. Biochemical Journal, 2016, 473(20): 3683-3704.

[5]    Lin S, Chen G, Liu X, Meng Q. Chimeric spider silk proteins mediated by intein result in artificial hybrid silks[J]. Biopolymers, 2016, 105(7): 385-392.

[4]    Otikovs M#, Chen G#, Nordling K, Landreh M, Meng Q, Jörnvall H, Kronqvist N, Rising A, Johansson J, Jaudzems K. Back Cover: Diversified structural basis of a conserved molecular mechanism for ph-dependent dimerization in spider silk N-terminal domains[J]. ChemBioChem, 2015, 16(12): 1720-1724. (#equal contributions)

[3]    Andersson M#, Chen G#, Otikovs M, Landreh M, Nordling K, Kronqvist N, Westermark P, Jörnvall H, Knight S, Ridderstråle Y, Holm L, Meng Q, Jaudzems K, Chesler M, Johansson J, Rising A. Carbonic anhydrase generates CO2 and H+ that drive spider silk formation via opposite effects on the terminal domains[J]. PLoS Biology, 2014, 12(8): e100192.(#equal contributions)

[2]    Kronqvist N, Otikovs M, Chmyrov V, Chen G, Andersson M, Nordling K, Landreh M, Sarr M, Jörnvall H, Wennmalm S, Widengren J, Meng Q, Rising A, Otzen D, Knight SD, Jaudzems K, Johansson J. Sequential pH-driven dimerization and stabilization of the N-terminal domain enables rapid spider silk formation[J]. Nature communications, 2014, 5: 3254.

[1]    Chen G, Liu X, Zhang Y, Lin S, Yang Z, Johansson J, Rising A, Meng Q. Full-length minor ampullate spidroin gene sequence[J]. PLoS ONE, 2012, 7(12): e52293.

 

Gene and structure deposition

Genes

  1. Araneus ventricosus clone F29-0811 minor ampullate spidroin gene, complete cds (NCBI accession number JX513956). 32513 bp, DNA, 2012.
  2. A. ventricosus clone AvMiSp2 minor ampullate spidroin mRNA, partial cds (NCBI accession number JX513955). 239 bp, mRNA, 2012.
  3. A. ventricosus clone AvMiSp1 minor ampullate spidroin mRNA, partial cds (NCBI accession number JX513954). 370 bp, mRNA, 2012.
  4. Argiope amoena tubuliform spidroin 1 (TuSp1) mRNA, partial cds. (NCBI accession number JQ291306). 1273 bp, mRNA, 2012.
  5. A. ventricosus aciniform spidroin 1 (AcSp1) mRNA, partial cds (NCBI accession number HQ008714). 6072 bp, mRNA, 2016.
  6. Argiope amoena aciniform spidroin 1 (AcSp1) mRNA, partial cds. (NCBI accession number HQ008715). 3216 bp, mRNA, 2016.

Structures

  1. NMR structure of C-terminal domain from A. ventricosus minor ampullate spidroin (MiSp) (PDB ID: 2MFZ). 2014.
  2. NMR structure of N-terminal domain from A. ventricosus minor ampullate spidroin (MiSp) at pH 7.2 (PDB ID: 2MX8). 2015.
  3. NMR structure of N-terminal domain from A. ventricosus minor ampullate spidroin (MiSp) at pH 5.5 (PDB ID: 2MX9). 2015.
  4. EM model of recombinant human Bri2 BRICHOS domain, oligomeric state (EMDB accession code: EMD-3918). 2017.
  5. EM model of recombinant human Bri2 BRICHOS D148N mutation, oligomeric state (EMDB accession code: EMD-13005). 2021.
  6. Cryo-EM structural model of recombinant human Bri2 BRICHOS oligomers (EMDB accession code: EMD-13866; PDB accession code: 7Q8X). 2022.

Academic honours, awards and prizes

Honours

Biträdande Lektor position at KI (Stockholm, Sweden), 2019

Commissions of trust

Grant review

  1. Austrian Science Fund (FWF) in the frame of the programme for funding patient oriented clinical research (KLIF).

Journal editorial board

  1. Young Editorial Board of Military Medical Research
  2. Editorial Board Member for Scientific Reports
  3. Editorial Board (Review Editor) for Frontiers in Molecular Bioscience
  4. Editorial Board (Review Editor) for Frontiers in Aging Neuroscience

Funding

Our projects are financially supported by Alzheimer's Association Research Grant (U.S.), Petrus och Augusta Hedlunds Stiftelse, Åke Wibergs stiftelse, Åhlén-stiftelsens Olle Engkvists Stiftelse, Alzheimerfonden, Stiftelsen Sigurd och Elsa Goljes Minne, Loo and Hans Osterman Foundation for Medical Research, Gun and Bertil Stohne's Foundation, Magnus Bergvalls Stiftelse, Karolinska Institutet Research Foundation Grants, Foundation for Geriatric Diseases at Karolinska Institutet, and Stiftelsen för Gamla Tjänarinnor.