Objective In kinesin-3,the neck coil correlates with the following segments to form an extended neck that contains a characteristic hinge diverse from a proline in KIF13B to a long flexible linker in KIF1A.The functio...Objective In kinesin-3,the neck coil correlates with the following segments to form an extended neck that contains a characteristic hinge diverse from a proline in KIF13B to a long flexible linker in KIF1A.The function of this neck hinge for controlling processive movement,however,remains unclear.Methods We made a series of modifications to the neck hinges of KIF13B and KIF1A and tested their movement using a single-molecule motility assay.Results In KIF13B,the insertion of flexible residues before or after the proline differentially impacts the processivity or velocity,while the removal of this proline increases the both.In KIF1A,the deletion of entire flexible neck hinge merely enhances the processivity.The engineering of these hinge-truncated necks of kinesin-3 into kinesin-1 similarly boosts the processive movement of kinesin-1.Conclusion The neck hinge in kinesin-3 controls its processive movement and proper modifications tune the motor motility,which provides a novel strategy to reshape the processive movement of kinesin motors.展开更多
Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal solid tumor with a high mortality rate. Conventional cancertreatments, including surgery, radiotherapy, and chemotherapy, primarily target cancer...Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal solid tumor with a high mortality rate. Conventional cancertreatments, including surgery, radiotherapy, and chemotherapy, primarily target cancer cell eradication. However, uncontrolled proliferation and metabolic activities of these cells result in abnormalities in nutrient levels, hypoxia, and immunosuppression within the tumor microenvironment (TME). These factors constrain the efficacy of traditional treatments by promoting drug resistance, recurrence, and metastasis. Nanomaterials (NMs), such as nanozymes, can exhibit enzymatic activity similar to that of natural enzymes and offer a promising avenuefor the direct modification of the TME through catalytic oxidation-reduction processes. Moreover, they can serve as sensitizers or drug deliverycarriers, enhancing the efficacy of traditional treatment methods. Recently, NMs have garnered significant attention from oncologists. Thisreview begins with an overview of the composition and unique characteristics of the TME. Subsequently, we comprehensively exploredthe application of NMs in the treatment of HNSCC. Finally, we discuss the potential prospects and challenges associated with usingNMs in biomedical research.展开更多
Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases.However,the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unkn...Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases.However,the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown.In this study,we demonstrated that S-nitrosoglutathione reductase(GSNOR)deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1βexpression levels and interleukin-1β(IL-1β)secretion in response to NLRP3 inflammasome stimulation.Furthermore,in vivo experiments utilizing Gsnor^(−/−)mice revealed increased disease severity in both lipopolysaccharide(LPS)-induced septic shock and dextran sodium sulfate(DSS)-induced colitis models.Additionally,we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor^(−/−)Nlrp3^(−/−)double-knockout(DKO)mice.Mechanistically,GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14(MAPK14)at the Cys211 residue and augments MAPK14 kinase activity,thereby promoting Nlrp3 and Il-1βtranscription and stimulating NLRP3 inflammasome activity.Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.展开更多
The abundance of molecules on early Earth likely enabled a wide range of prebiotic chemistry,with peptides playing a key role in the development of early life forms and the evolution of metabolic pathways.Among peptid...The abundance of molecules on early Earth likely enabled a wide range of prebiotic chemistry,with peptides playing a key role in the development of early life forms and the evolution of metabolic pathways.Among peptides,those with enzyme-like activities occupy a unique position between peptides and enzymes,combining both structural flexibility and catalytic functionality.However,their full potential remains largely untapped.Further exploration of these enzyme-like peptides at the nanoscale could provide valuable insights into modern nanotechnology,biomedicine,and even the origins of life.Hence,this review introduces the groundbreaking concept of“peptide nanozymes(PepNzymes)”,which includes single peptides exhibiting enzyme-like activities,peptide-based nanostructures with enzyme-like activities,and peptide-based nanozymes,thus enabling the investigation of biological phenomena at nanoscale dimensions.Through the rational design of enzyme-like peptides or their assembly with nanostructures and nanozymes,researchers have found or created PepNzymes capable of catalyzing a wide range of reactions.By scrutinizing the interactions between the structures and enzyme-like activities of PepNzymes,we have gained valuable insights into the underlying mechanisms governing enzyme-like activities.Generally,PepNzymes play a crucial role in biological processes by facilitating small-scale enzyme-like reactions,speeding up molecular oxidation-reduction,cleavage,and synthesis reactions,leveraging the functional properties of peptides,and creating a stable microenvironment,among other functions.These discoveries make PepNzymes useful for diagnostics,cellular imaging,antimicrobial therapy,tissue engineering,anti-tumor treatments,and more while pointing out opportunities.Overall,this research provides a significant journey of PepNzymes’potential in various biomedical applications,pushing them towards new advancements.展开更多
Thousands of nuclear-encoded proteins are transported into chloroplasts through the TOC–TIC translocon that spans the chloroplast envelope membranes.A motor complex pulls the translocated proteins out of the TOC–TIC...Thousands of nuclear-encoded proteins are transported into chloroplasts through the TOC–TIC translocon that spans the chloroplast envelope membranes.A motor complex pulls the translocated proteins out of the TOC–TIC complex into the chloroplast stroma by hydrolyzing ATP.The Orf2971–FtsHi complex has been suggested to serve as the ATP-hydrolyzing motor in Chlamydomonas reinhardtii,but little is known about its architecture and assembly.Here,we report the 3.2-Åresolution structure of the Chlamydomonas Orf2971–FtsHi complex.The 20-subunit complex spans the chloroplast inner envelope,with two bulky modules protruding into the intermembrane space and stromal matrix.Six subunits form a hetero-hexamer that potentially provides the pulling force through ATP hydrolysis.The remaining subunits,including potential enzymes/chaperones,likely facilitate the complex assembly and regulate its proper function.Taken together,our results provide the structural foundation for a mechanistic understanding of chloroplast protein translocation.展开更多
文摘Objective In kinesin-3,the neck coil correlates with the following segments to form an extended neck that contains a characteristic hinge diverse from a proline in KIF13B to a long flexible linker in KIF1A.The function of this neck hinge for controlling processive movement,however,remains unclear.Methods We made a series of modifications to the neck hinges of KIF13B and KIF1A and tested their movement using a single-molecule motility assay.Results In KIF13B,the insertion of flexible residues before or after the proline differentially impacts the processivity or velocity,while the removal of this proline increases the both.In KIF1A,the deletion of entire flexible neck hinge merely enhances the processivity.The engineering of these hinge-truncated necks of kinesin-3 into kinesin-1 similarly boosts the processive movement of kinesin-1.Conclusion The neck hinge in kinesin-3 controls its processive movement and proper modifications tune the motor motility,which provides a novel strategy to reshape the processive movement of kinesin motors.
基金supported by medical science research joint construction project of Henan(71188)Henan Provincial Department of Education under grant no.21B320008.
文摘Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal solid tumor with a high mortality rate. Conventional cancertreatments, including surgery, radiotherapy, and chemotherapy, primarily target cancer cell eradication. However, uncontrolled proliferation and metabolic activities of these cells result in abnormalities in nutrient levels, hypoxia, and immunosuppression within the tumor microenvironment (TME). These factors constrain the efficacy of traditional treatments by promoting drug resistance, recurrence, and metastasis. Nanomaterials (NMs), such as nanozymes, can exhibit enzymatic activity similar to that of natural enzymes and offer a promising avenuefor the direct modification of the TME through catalytic oxidation-reduction processes. Moreover, they can serve as sensitizers or drug deliverycarriers, enhancing the efficacy of traditional treatment methods. Recently, NMs have garnered significant attention from oncologists. Thisreview begins with an overview of the composition and unique characteristics of the TME. Subsequently, we comprehensively exploredthe application of NMs in the treatment of HNSCC. Finally, we discuss the potential prospects and challenges associated with usingNMs in biomedical research.
基金Yunnan Fundamental Research Project(202305AH340006)National Natural Science Foundation of China(32201018)+1 种基金Basic Research Program and Key Project of Yunnan Province(202301AW070013 and 202003AD150009)Youth Innovation Promotion Association(2023403).
文摘Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases.However,the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown.In this study,we demonstrated that S-nitrosoglutathione reductase(GSNOR)deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1βexpression levels and interleukin-1β(IL-1β)secretion in response to NLRP3 inflammasome stimulation.Furthermore,in vivo experiments utilizing Gsnor^(−/−)mice revealed increased disease severity in both lipopolysaccharide(LPS)-induced septic shock and dextran sodium sulfate(DSS)-induced colitis models.Additionally,we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor^(−/−)Nlrp3^(−/−)double-knockout(DKO)mice.Mechanistically,GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14(MAPK14)at the Cys211 residue and augments MAPK14 kinase activity,thereby promoting Nlrp3 and Il-1βtranscription and stimulating NLRP3 inflammasome activity.Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.
基金funded by the Key Project of the Joint Fund for Regional Innovation and Development of the National Natural Science Foundation of China(U23A20686)the Key Laboratory of Biomacromolecules,Chinese Academy of Sciences(ZGD-2023-03)+1 种基金the Joint Funds for the Innovation of Science and Technology,Fujian Province(2023Y9226)the Introduced High-Level Talent Team Project of Quanzhou City(2023CT008).
文摘The abundance of molecules on early Earth likely enabled a wide range of prebiotic chemistry,with peptides playing a key role in the development of early life forms and the evolution of metabolic pathways.Among peptides,those with enzyme-like activities occupy a unique position between peptides and enzymes,combining both structural flexibility and catalytic functionality.However,their full potential remains largely untapped.Further exploration of these enzyme-like peptides at the nanoscale could provide valuable insights into modern nanotechnology,biomedicine,and even the origins of life.Hence,this review introduces the groundbreaking concept of“peptide nanozymes(PepNzymes)”,which includes single peptides exhibiting enzyme-like activities,peptide-based nanostructures with enzyme-like activities,and peptide-based nanozymes,thus enabling the investigation of biological phenomena at nanoscale dimensions.Through the rational design of enzyme-like peptides or their assembly with nanostructures and nanozymes,researchers have found or created PepNzymes capable of catalyzing a wide range of reactions.By scrutinizing the interactions between the structures and enzyme-like activities of PepNzymes,we have gained valuable insights into the underlying mechanisms governing enzyme-like activities.Generally,PepNzymes play a crucial role in biological processes by facilitating small-scale enzyme-like reactions,speeding up molecular oxidation-reduction,cleavage,and synthesis reactions,leveraging the functional properties of peptides,and creating a stable microenvironment,among other functions.These discoveries make PepNzymes useful for diagnostics,cellular imaging,antimicrobial therapy,tissue engineering,anti-tumor treatments,and more while pointing out opportunities.Overall,this research provides a significant journey of PepNzymes’potential in various biomedical applications,pushing them towards new advancements.
基金funded by the Strategic Priority Research Program of CAS(XDB37020101)the National Key R&D Program of China(2021YFA0910800)+3 种基金the National Natural Science Foundation of China(31930064)the Youth Innovation Promotion Association,Chinese Academy of Sciences(Y2022038)the Regional Joint Key Projects of the National Foundation of China(U22A20445)the Natural Science Foundation of Shandong Province(ZR2023ZD30).
文摘Thousands of nuclear-encoded proteins are transported into chloroplasts through the TOC–TIC translocon that spans the chloroplast envelope membranes.A motor complex pulls the translocated proteins out of the TOC–TIC complex into the chloroplast stroma by hydrolyzing ATP.The Orf2971–FtsHi complex has been suggested to serve as the ATP-hydrolyzing motor in Chlamydomonas reinhardtii,but little is known about its architecture and assembly.Here,we report the 3.2-Åresolution structure of the Chlamydomonas Orf2971–FtsHi complex.The 20-subunit complex spans the chloroplast inner envelope,with two bulky modules protruding into the intermembrane space and stromal matrix.Six subunits form a hetero-hexamer that potentially provides the pulling force through ATP hydrolysis.The remaining subunits,including potential enzymes/chaperones,likely facilitate the complex assembly and regulate its proper function.Taken together,our results provide the structural foundation for a mechanistic understanding of chloroplast protein translocation.