In the last decades,the role of the prion protein(PrP) in neurodegenerative diseases has been intensively investigated,initially in prion diseases of humans(e.g., Creutzfeldt-J akob disease) and animals(e.g.,scrapie i...In the last decades,the role of the prion protein(PrP) in neurodegenerative diseases has been intensively investigated,initially in prion diseases of humans(e.g., Creutzfeldt-J akob disease) and animals(e.g.,scrapie in sheep,chronic wasting disease in deer and elk,or "mad cow disease" in cattle).Templated misfolding of physiological cellular prion protein(PrPC) into an aggregation-prone isoform(termed PrP "Scrapie"(PrPSc)),self-re plication and spreading of the latter inside the brain and to peripheral tissues,and the associated formation of infectious proteopathic seeds(termed "prions")are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies.Late r,key roles of the correctly folded PrPCwere identified in more common human brain diseases(such as Alzheimer s disease or Parkinson’s disease) associated with the misfolding and/or accumulation of other proteins(such as amyloid-β,tau or α-synuclein,respectively).PrPChas also been linked with n euro protective and regenerative functions,for instance in hypoxic/ischemic conditions such as stroke.However,despite a mixed "bouquet" of suggested functions,our understanding of pathological and,especially,physiological roles played by PrPCin the brain and beyond is ce rtainly incomplete.Interactions with various other proteins at the cell surfa ce or within intracellular compartments may account for the functional diversity linked with PrPC.Moreover,conserved endogenous proteolytic processing of PrPCgenerates seve ral defined PrPCfragments,possibly holding intrinsic functions in physiological and pathological conditions,thus making the "true and complete biology" of this protein more complicated to be elucidated.Here,we focus on one of those released PrPCfragments,namely shed PrP(sPrP),generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surfa ce.Similar to other soluble PrP fragments(such as the N1 fragment representing PrP’s released N-terminal tail upon the major α-cleavage event)or expe rimentally employed recombinant PrP,sPrP is being suggested to act n euro protective in Alzheimer’s disease and other protein misfolding diseases.Seve ral lines of evidence on extracellular PrPC(fragments) suggest that induction of PrPCrelease co uld be a future therapeutic option in various brain disorders.Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM 10,based on ligands binding to cell surface PrPC,may further set the stage for research into this direction.展开更多
Dear Editor,Alzheimer’s disease(AD)remains devastating neurodegenerative disorder with enormous societal and clinical impact,largely due to the challenge of detecting pathogenies changes early and the absence of effe...Dear Editor,Alzheimer’s disease(AD)remains devastating neurodegenerative disorder with enormous societal and clinical impact,largely due to the challenge of detecting pathogenies changes early and the absence of effective disease-modifying treatments.Central to AD pathogenic is the dysregulated proteolytic processing of amyloid precursor protein(APP),primarily mediated byβ-site APP cleaving enzyme(BACE1)which initiates the accumulation of amyloid-β(Αβ)peptides.The enzymesα-secretase(ADAM10)and the Aβ-degrading neprilysin are widely recognized as critical intervention points.Yet,there is a pressing need for probes that can both sensitively detect and modulate these targets in complex biological settings.1,2 Current imaging and therapeutic agents often lack both the optical responsiveness and biochemical selectivity needed for early AD intervention.Integrating optical sensing with target-specific binding,supported by in silico docking and structure-based screening,now offer rational path toward precision for theranostic molecular probe.展开更多
Transcription factors constitute numerous signal transduction networks and play a central role in gene expression regulation. Recent studies have shown that a limited portion of transcription factors are anchored in t...Transcription factors constitute numerous signal transduction networks and play a central role in gene expression regulation. Recent studies have shown that a limited portion of transcription factors are anchored in the cellular membrane, storing as dormant forms. Upon exposure to environmental and developmental cues, these transcription factors are released from the membrane and translocated to the nucleus, where they regulate associated target genes. As this process skips both transcriptional and translational regulations, it guarantees prompt response to external and internal signals. Membrane- bound transcription factors （MTFs） undergo several unique steps that are not involved in the action of canonical nuclear transcription factors： proteolytic processing and intracellular movement. Recently, alternative splicing has also emerged as a mechanism to liberate MTFs from the cellular membranes, establishing an additional activation scheme independent of proteolytic processing. Multiple layers of MTF regulation add complexity to transcriptional regulatory scheme and ensure elaborate action of MTFs. In this review, we provide an overview of recent findings on MTFs in plants and highlight the molecular mechanisms underlying MTF liberation from cellular membranes with an emphasis on intracellular movement.展开更多
1-Aminocyclopropane-1-carboxylic acid （ACC） synthase （ACS） is the principal enzyme in phytohormone ethylene biosynthesis. Previous studies have shown that the hypervariable C-terminus of ACS is proteolytically pro...1-Aminocyclopropane-1-carboxylic acid （ACC） synthase （ACS） is the principal enzyme in phytohormone ethylene biosynthesis. Previous studies have shown that the hypervariable C-terminus of ACS is proteolytically processed in vivo. However, the protease responsible for this has not yet been identified. In the present study, we investigated the processing of the 55-kDa full-length tomato ACS （LeACS2） into 52-, 50- and 49-kDa truncated isoforms in ripening tomato （Lycopersicon esculentum Mill. cv. Cooperation 903） fruit using the sodium dodecyl sulfate-boiling method. Meanwhile, an LeACS2-processing protease was purified via multi-step column chromatography from tomato fruit. Subsequent biochemical analysis of the 64-kDa purified protease revealed that it is a metalloprotease active at multiple cleavage sites within the hypervariable C-terminus of LeACS2. N-terminal sequencing and matrix-assisted laser desorption/ionization time-of-flight analysis indicated that the LeACS2-processing metalloprotease cleaves at the C-terminal sites Lys^438, Glu^447, Lys^448, Asn^456, Ser^460, Ser^462, Lys^463, and Leu^474, but does not cleave the N- terminus of LeACS2. Four C-terminus-deleted （26-50 amino acids） LeACS2 fusion proteins were overproduced and subjected to proteolysis by this metalloprotease to identify the multiple cleavage sites located on the N-terminal side of the phosphorylation site Ser^460. The results indisputably confirmed the presence of cleavage sites within the region between the α-helix domain （H14） and Ser^460 for this metalloprotease. Furthermore, the resulting C-terminally truncated LeACS2 isoforms were active enzymatically. Because this protease could produce LeACS2 isoforms in vitro similar to those detected in vivo, it is proposed that this metalloprotease may be involved in the proteolysis of LeACS2 in vivo.展开更多
Peptide hormones are defined as small secreted polypeptide-based intercellular communication signal molecules.Such peptide hormones are encoded by nuclear genes,and often go through proteolytic processing of prepropro...Peptide hormones are defined as small secreted polypeptide-based intercellular communication signal molecules.Such peptide hormones are encoded by nuclear genes,and often go through proteolytic processing of preproproteins and post-translational modifications.Most peptide hormones are secreted out of the cell to interact with membrane-associated receptors in neighboring cells,and subsequently activate signal transductions,leading to changes in gene expression and cellular responses.Since the discovery of the first plant peptide hormone,systemin,in tomato in 1991,putative peptide hormones have continuously been identified in different plant species,showing their importance in both short-and long-range signal transductions.The roles of peptide hormones are implicated in,but not limited to,processes such as self-incompatibility,pollination,fertilization,embryogenesis,endosperm development,stem cell regulation,plant architecture,tissue differentiation,organogenesis,dehiscence,senescence,plantpathogen and plant-insect interactions,and stress responses.This article,collectively written by researchers in this field,aims to provide a general overview for the discoveries,functions,chemical natures,transcriptional regulations,and post-translational modifications of peptide hormones in plants.We also updated recent discoveries in receptor kinases underlying the peptide hormone sensing and down-stream signal pathways.Future prospective and challenges will also be discussed at the end of the article.展开更多
基金supported by funding from the Creutzfeldt-Jakob Disease FoundationInc.(USA)+4 种基金the Alzheimer Forschung Initiative (AFI e.V.,Germany)the Werner-Otto-Stiftung (Hamburg,Germany)(all to HCA)the China Scholarship Council (to FS)European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie Grant Agreement N°101030402 (to AMA)Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Center (CRC) 877"Proteolysis as a regulatory event in pathophysiology"(to MG)。
文摘In the last decades,the role of the prion protein(PrP) in neurodegenerative diseases has been intensively investigated,initially in prion diseases of humans(e.g., Creutzfeldt-J akob disease) and animals(e.g.,scrapie in sheep,chronic wasting disease in deer and elk,or "mad cow disease" in cattle).Templated misfolding of physiological cellular prion protein(PrPC) into an aggregation-prone isoform(termed PrP "Scrapie"(PrPSc)),self-re plication and spreading of the latter inside the brain and to peripheral tissues,and the associated formation of infectious proteopathic seeds(termed "prions")are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies.Late r,key roles of the correctly folded PrPCwere identified in more common human brain diseases(such as Alzheimer s disease or Parkinson’s disease) associated with the misfolding and/or accumulation of other proteins(such as amyloid-β,tau or α-synuclein,respectively).PrPChas also been linked with n euro protective and regenerative functions,for instance in hypoxic/ischemic conditions such as stroke.However,despite a mixed "bouquet" of suggested functions,our understanding of pathological and,especially,physiological roles played by PrPCin the brain and beyond is ce rtainly incomplete.Interactions with various other proteins at the cell surfa ce or within intracellular compartments may account for the functional diversity linked with PrPC.Moreover,conserved endogenous proteolytic processing of PrPCgenerates seve ral defined PrPCfragments,possibly holding intrinsic functions in physiological and pathological conditions,thus making the "true and complete biology" of this protein more complicated to be elucidated.Here,we focus on one of those released PrPCfragments,namely shed PrP(sPrP),generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surfa ce.Similar to other soluble PrP fragments(such as the N1 fragment representing PrP’s released N-terminal tail upon the major α-cleavage event)or expe rimentally employed recombinant PrP,sPrP is being suggested to act n euro protective in Alzheimer’s disease and other protein misfolding diseases.Seve ral lines of evidence on extracellular PrPC(fragments) suggest that induction of PrPCrelease co uld be a future therapeutic option in various brain disorders.Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM 10,based on ligands binding to cell surface PrPC,may further set the stage for research into this direction.
基金supported by the Gachon University research fund of 2020 (GCU-202008430008).
文摘Dear Editor,Alzheimer’s disease(AD)remains devastating neurodegenerative disorder with enormous societal and clinical impact,largely due to the challenge of detecting pathogenies changes early and the absence of effective disease-modifying treatments.Central to AD pathogenic is the dysregulated proteolytic processing of amyloid precursor protein(APP),primarily mediated byβ-site APP cleaving enzyme(BACE1)which initiates the accumulation of amyloid-β(Αβ)peptides.The enzymesα-secretase(ADAM10)and the Aβ-degrading neprilysin are widely recognized as critical intervention points.Yet,there is a pressing need for probes that can both sensitively detect and modulate these targets in complex biological settings.1,2 Current imaging and therapeutic agents often lack both the optical responsiveness and biochemical selectivity needed for early AD intervention.Integrating optical sensing with target-specific binding,supported by in silico docking and structure-based screening,now offer rational path toward precision for theranostic molecular probe.
基金supported by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2013R1A1A1004831)research funds of Chonbuk National University in 2012
文摘Transcription factors constitute numerous signal transduction networks and play a central role in gene expression regulation. Recent studies have shown that a limited portion of transcription factors are anchored in the cellular membrane, storing as dormant forms. Upon exposure to environmental and developmental cues, these transcription factors are released from the membrane and translocated to the nucleus, where they regulate associated target genes. As this process skips both transcriptional and translational regulations, it guarantees prompt response to external and internal signals. Membrane- bound transcription factors （MTFs） undergo several unique steps that are not involved in the action of canonical nuclear transcription factors： proteolytic processing and intracellular movement. Recently, alternative splicing has also emerged as a mechanism to liberate MTFs from the cellular membranes, establishing an additional activation scheme independent of proteolytic processing. Multiple layers of MTF regulation add complexity to transcriptional regulatory scheme and ensure elaborate action of MTFs. In this review, we provide an overview of recent findings on MTFs in plants and highlight the molecular mechanisms underlying MTF liberation from cellular membranes with an emphasis on intracellular movement.
基金Supported by Hong Kong Research Grant Council （HKUST6102/02M and HKUST6105/01M） and the National Natural Science Foundation of China （30129001）.
文摘1-Aminocyclopropane-1-carboxylic acid （ACC） synthase （ACS） is the principal enzyme in phytohormone ethylene biosynthesis. Previous studies have shown that the hypervariable C-terminus of ACS is proteolytically processed in vivo. However, the protease responsible for this has not yet been identified. In the present study, we investigated the processing of the 55-kDa full-length tomato ACS （LeACS2） into 52-, 50- and 49-kDa truncated isoforms in ripening tomato （Lycopersicon esculentum Mill. cv. Cooperation 903） fruit using the sodium dodecyl sulfate-boiling method. Meanwhile, an LeACS2-processing protease was purified via multi-step column chromatography from tomato fruit. Subsequent biochemical analysis of the 64-kDa purified protease revealed that it is a metalloprotease active at multiple cleavage sites within the hypervariable C-terminus of LeACS2. N-terminal sequencing and matrix-assisted laser desorption/ionization time-of-flight analysis indicated that the LeACS2-processing metalloprotease cleaves at the C-terminal sites Lys^438, Glu^447, Lys^448, Asn^456, Ser^460, Ser^462, Lys^463, and Leu^474, but does not cleave the N- terminus of LeACS2. Four C-terminus-deleted （26-50 amino acids） LeACS2 fusion proteins were overproduced and subjected to proteolysis by this metalloprotease to identify the multiple cleavage sites located on the N-terminal side of the phosphorylation site Ser^460. The results indisputably confirmed the presence of cleavage sites within the region between the α-helix domain （H14） and Ser^460 for this metalloprotease. Furthermore, the resulting C-terminally truncated LeACS2 isoforms were active enzymatically. Because this protease could produce LeACS2 isoforms in vitro similar to those detected in vivo, it is proposed that this metalloprotease may be involved in the proteolysis of LeACS2 in vivo.
基金supported by the National Natural Science Foundation of China(32270332 to Y.G.,32370850 to G.W.,32170332 to X.G.,32230009 to Cao Li,32230077 to C-M.L,U22A20474 and 32172073 to L.W)the Agricultural Science and Technology Innovation Program of China,Chinese Academy of Agricultural Sciences(ASTIP-TRI02 to Y.G.)+3 种基金the Natural Science Foundation of Shaanxi(2020JC-29 and 2023-JC-ZD-09 to G.W.)the Fundamental Research Funds for the Central Universities(GK202402003 to G.W.)the Foundation of Science and Technology of Gansu Province(21ZDKA0016 and 22ZD6NA049 to X.G.)the National Key R&D Program of China(2021YFF1000201 to C-M.L.).
文摘Peptide hormones are defined as small secreted polypeptide-based intercellular communication signal molecules.Such peptide hormones are encoded by nuclear genes,and often go through proteolytic processing of preproproteins and post-translational modifications.Most peptide hormones are secreted out of the cell to interact with membrane-associated receptors in neighboring cells,and subsequently activate signal transductions,leading to changes in gene expression and cellular responses.Since the discovery of the first plant peptide hormone,systemin,in tomato in 1991,putative peptide hormones have continuously been identified in different plant species,showing their importance in both short-and long-range signal transductions.The roles of peptide hormones are implicated in,but not limited to,processes such as self-incompatibility,pollination,fertilization,embryogenesis,endosperm development,stem cell regulation,plant architecture,tissue differentiation,organogenesis,dehiscence,senescence,plantpathogen and plant-insect interactions,and stress responses.This article,collectively written by researchers in this field,aims to provide a general overview for the discoveries,functions,chemical natures,transcriptional regulations,and post-translational modifications of peptide hormones in plants.We also updated recent discoveries in receptor kinases underlying the peptide hormone sensing and down-stream signal pathways.Future prospective and challenges will also be discussed at the end of the article.
