Mouse Kif1c Conditional Knockout Project (CRISPR/Cas9)
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HOOK3 Is a Scaffold for the Opposite-Polarity Microtubule-Based
bioRxiv preprint doi: https://doi.org/10.1101/508887; this version posted December 31, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. HOOK3 is a scaffold for the opposite-polarity microtubule-based motors cytoplasmic dynein and KIF1C Agnieszka A. Kendrick1, William B. Redwine1,2†, Phuoc Tien Tran1‡, Laura Pontano Vaites2, Monika Dzieciatkowska4, J. Wade Harper2, and Samara L. Reck-Peterson1,3,5 1Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093. 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115. 3Section of Cell and Developmental Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093. 4Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045. 5Howard Hughes Medical Institute †Present address: Stowers Institute for Medical Research, Kansas City, MO 64110 ‡Present address: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138. *Correspondence to: Samara Reck-Peterson 9500 Gilman Drive, Leichtag 482 La Jolla CA, 92093 [email protected]; https://orcid.org/0000-0002-1553-465X 1 bioRxiv preprint doi: https://doi.org/10.1101/508887; this version posted December 31, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. -
Product Datasheet KIF1C Antibody NB100-57510
Product Datasheet KIF1C Antibody NB100-57510 Unit Size: 0.1 ml Store at 4C. Do not freeze. Reviews: 1 Publications: 1 Protocols, Publications, Related Products, Reviews, Research Tools and Images at: www.novusbio.com/NB100-57510 Updated 3/16/2021 v.20.1 Earn rewards for product reviews and publications. Submit a publication at www.novusbio.com/publications Submit a review at www.novusbio.com/reviews/destination/NB100-57510 Page 1 of 3 v.20.1 Updated 3/16/2021 NB100-57510 KIF1C Antibody Product Information Unit Size 0.1 ml Concentration 0.2 mg/ml Storage Store at 4C. Do not freeze. Clonality Polyclonal Preservative 0.09% Sodium Azide Isotype IgG Purity Immunogen affinity purified Buffer TBS and 0.1% BSA Product Description Host Rabbit Gene ID 10749 Gene Symbol KIF1C Species Human, Mouse Immunogen The immunogen recognized by this antibody maps to a region between residue 1053 and the C-terminus (residue 1103) of human kinesin family member 1C (lethal toxin sensitivity 1) using the numbering given in entry NP_006603.2 (GeneID 10749). Product Application Details Applications Western Blot, Immunoprecipitation Recommended Dilutions Western Blot 1:2000-1:10000, Immunoprecipitation 2 - 5 ug/mg lysate Page 2 of 3 v.20.1 Updated 3/16/2021 Images Western Blot: KIF1C Antibody [NB100-57510] - KIF1C is a novel HOOK3 -interacting protein.sfGFP-3xFLAG and full length (FL) HOOK3, HOOK3 (1-552), and HOOK3 (553-718) all tagged with sfGFP and 3xFLAG were immunoprecipitated with alpha-FLAG antibodies from transiently transfected HEK-293T cells. Western blots with alpha-HC, alpha- FAM160A2, alpha-KIF1C, and alpha-FLAG antibodies were used to determine which proteins co-immunoprecipitated with each HOOK3 construct.DOI:http://dx.doi.org/10.7554/eLife.28257.015 Image collected and cropped by CiteAb from the following publication (https://elifesciences.org/articles/28257), licensed under a CC-BY licence. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
S41467-020-18249-3.Pdf
ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible. -
The Rab6-Regulated KIF1C Kinesin Motor Domain Contributes to Golgi Organization Peter L Lee, Maikke B Ohlson†, Suzanne R Pfeffer*
RESEARCH ARTICLE elifesciences.org The Rab6-regulated KIF1C kinesin motor domain contributes to Golgi organization Peter L Lee, Maikke B Ohlson†, Suzanne R Pfeffer* Department of Biochemistry, Stanford University School of Medicine, Stanford, United States Abstract Most kinesins transport cargoes bound to their C-termini and use N-terminal motor domains to move along microtubules. We report here a novel function for KIF1C: it transports Rab6A-vesicles and can influence Golgi complex organization. These activities correlate with KIF1C’s capacity to bind the Golgi protein Rab6A directly, both via its motor domain and C-terminus. Rab6A binding to the motor domain inhibits microtubule interaction in vitro and in cells, decreasing the amount of motile KIF1C. KIF1C depletion slows protein delivery to the cell surface, interferes with vesicle motility, and triggers Golgi fragmentation. KIF1C can protect Golgi membranes from fragmentation in cells lacking an intact microtubule network. Rescue of fragmentation requires sequences that enable KIF1C to bind Rab6A at both ends, but not KIF1C motor function. Rab6A binding to KIF1C’s motor domain represents an entirely new mode of regulation for a kinesin motor, and likely has important consequences for KIF1C’s cellular functions. DOI: 10.7554/eLife.06029.001 *For correspondence: pfeffer@ stanford.edu Introduction Kinesin superfamily proteins (KIFs) are microtubule-based motors that are responsible for the Present address: †Genentech, motility of membrane-bound compartments and transport vesicles (Hirokawa et al., 2009b; South San Francisco, United States Verhey and Hammond, 2009). Of fundamental interest is how these motor proteins link to specific membrane cargoes and how they are regulated. -
The Kinesin Superfamily Handbook Transporter, Creator, Destroyer
The Kinesin Superfamily Handbook Transporter, Creator, Destroyer Edited by Claire T. Friel First edition published 2020 ISBN: 978-1-138-58956-8 (hbk) ISBN: 978-0-429-49155-9 (ebk) 4 The Kinesin-3 Family Long-Distance Transporters Nida Siddiqui and Anne Straube CC BY-NC-ND 4.0 The Kinesin Superfamily Handbook The Kinesin-3 Family 4 Long-Distance Transporters Nida Siddiqui and Anne Straube CONTENTS 4.1 Example Family Members .............................................................................. 41 4.2 Structural Information .................................................................................... 41 4.3 Functional Properties ...................................................................................... 43 4.3.1 Autoinhibition of Kinesin-3 Motors and Their Activation .................45 4.4 Physiological Roles .........................................................................................46 4.4.1 Preference for Subsets of Microtubule Tracks .................................... 47 4.5 Involvement in Disease ...................................................................................48 Acknowledgements ..................................................................................................49 References ................................................................................................................49 The Kinesin-3s are a family of cargo transporters. They typically display highly processive plus-end-directed motion, either as dimers or in teams, formed via interaction with -
Hereditary Spastic Paraplegia: from Genes, Cells and Networks to Novel Pathways for Drug Discovery
brain sciences Review Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery Alan Mackay-Sim Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia; a.mackay-sim@griffith.edu.au Abstract: Hereditary spastic paraplegia (HSP) is a diverse group of Mendelian genetic disorders affect- ing the upper motor neurons, specifically degeneration of their distal axons in the corticospinal tract. Currently, there are 80 genes or genomic loci (genomic regions for which the causative gene has not been identified) associated with HSP diagnosis. HSP is therefore genetically very heterogeneous. Finding treatments for the HSPs is a daunting task: a rare disease made rarer by so many causative genes and many potential mutations in those genes in individual patients. Personalized medicine through genetic correction may be possible, but impractical as a generalized treatment strategy. The ideal treatments would be small molecules that are effective for people with different causative mutations. This requires identification of disease-associated cell dysfunctions shared across geno- types despite the large number of HSP genes that suggest a wide diversity of molecular and cellular mechanisms. This review highlights the shared dysfunctional phenotypes in patient-derived cells from patients with different causative mutations and uses bioinformatic analyses of the HSP genes to identify novel cell functions as potential targets for future drug treatments for multiple genotypes. Keywords: neurodegeneration; motor neuron disease; spastic paraplegia; endoplasmic reticulum; Citation: Mackay-Sim, A. Hereditary protein-protein interaction network Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery. Brain Sci. 2021, 11, 403. -
Data-Mining Approach for Screening of Rare Genetic Elements Associated
Turk J Biochem 2019; 44(6): 848–854 Research Article Muhammad Zubair Mahboob, Arslan Hamid, Nada Mushtaq, Sana Batool, Hina Batool, Nadia Zeeshan, Muhammad Ali, Kalsoom Sughra* and Naeem Mahmood Ashraf* Data-mining approach for screening of rare genetic elements associated with predisposition of prostate cancer in South-Asian populations Güney Asya Popülasyonlarında Prostat Kanseri Predispozisyonuyla İlişkili Nadir Genetik Elementlerin Taranmasında Veri Madenciliği Yaklaşımı https://doi.org/10.1515/tjb-2018-0454 Materials and methods: Genome-wide association studies Received November 9, 2018; accepted May 23, 2019; previously (GWAS) catalog and Gene Expression Omnibus (GEO) fur- published online August 30, 2019 nished PCa-related genetic studies. Database for Anno- Abstract tation, Visualization and Integrated Discovery (DAVID) functionally annotated these genes and wANNOVAR sep- Objective: Prostate cancer (PCa) is a complex heterogene- arated South Asian (SAS) populations – specific genetic ous disease and a major health risk to men throughout the factors at MAF threshold <0.05. world. The potential tumorigenic genetic hallmarks asso- Results: The study reports 195 genes as potential contribu- ciated with PCa include sustaining proliferative signaling, tors to prostate cancer in SAS populations. Some of iden- resisting cell death, aberrant androgen receptor signal- tified genes are PYGO2, RALBP1, RFX5, SLC22A3, VPS53, ing, androgen independence, and castration resistance. HMCN1 and KIF1C. Despite numerous comprehensive genome-wide associa- Conclusion: The identified genetic elements may assist in tion studies (GWAS), certain genetic elements associated development of population-specific screening and man- with PCa are still unknown. This situation demands more agement strategies for PCa. Moreover, this approach may systematic GWAS studies in different populations. -
Download Ppis for Each Single Seed, Thus Obtaining Each Seed’S Interactome (Ferrari Et Al., 2018)
bioRxiv preprint doi: https://doi.org/10.1101/2021.01.14.425874; this version posted January 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Integrating protein networks and machine learning for disease stratification in the Hereditary Spastic Paraplegias Nikoleta Vavouraki1,2, James E. Tomkins1, Eleanna Kara3, Henry Houlden3, John Hardy4, Marcus J. Tindall2,5, Patrick A. Lewis1,4,6, Claudia Manzoni1,7* Author Affiliations 1: Department of Pharmacy, University of Reading, Reading, RG6 6AH, United Kingdom 2: Department of Mathematics and Statistics, University of Reading, Reading, RG6 6AH, United Kingdom 3: Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom 4: Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom 5: Institute of Cardiovascular and Metabolic Research, University of Reading, Reading, RG6 6AS, United Kingdom 6: Department of Comparative Biomedical Sciences, Royal Veterinary College, London, NW1 0TU, United Kingdom 7: School of Pharmacy, University College London, London, WC1N 1AX, United Kingdom *Corresponding author: [email protected] Abstract The Hereditary Spastic Paraplegias are a group of neurodegenerative diseases characterized by spasticity and weakness in the lower body. Despite the identification of causative mutations in over 70 genes, the molecular aetiology remains unclear. Due to the combination of genetic diversity and variable clinical presentation, the Hereditary Spastic Paraplegias are a strong candidate for protein- protein interaction network analysis as a tool to understand disease mechanism(s) and to aid functional stratification of phenotypes. -
PTPN21 and Hook3 Relieve KIF1C Autoinhibition and Activate Intracellular Transport
ARTICLE https://doi.org/10.1038/s41467-019-10644-9 OPEN PTPN21 and Hook3 relieve KIF1C autoinhibition and activate intracellular transport Nida Siddiqui 1,2,5, Alexander James Zwetsloot 1,3,5, Alice Bachmann1,2, Daniel Roth 1,2, Hamdi Hussain 1,2, Jonathan Brandt 1,2, Irina Kaverina4 & Anne Straube 1,2 The kinesin-3 KIF1C is a fast organelle transporter implicated in the transport of dense core vesicles in neurons and the delivery of integrins to cell adhesions. Here we report the 1234567890():,; mechanisms of autoinhibition and release that control the activity of KIF1C. We show that the microtubule binding surface of KIF1C motor domain interacts with its stalk and that these autoinhibitory interactions are released upon binding of protein tyrosine phosphatase PTPN21. The FERM domain of PTPN21 stimulates dense core vesicle transport in primary hippocampal neurons and rescues integrin trafficking in KIF1C-depleted cells. In vitro, human full-length KIF1C is a processive, plus-end directed motor. Its landing rate onto microtubules increases in the presence of either PTPN21 FERM domain or the cargo adapter Hook3 that binds the same region of KIF1C tail. This autoinhibition release mechanism allows cargo- activated transport and might enable motors to participate in bidirectional cargo transport without undertaking a tug-of-war. 1 Centre for Mechanochemical Cell Biology, University of Warwick, Coventry CV4 7AL, UK. 2 Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK. 3 MRC-DTP in Interdisciplinary Biomedical Research, Warwick Medical School, Coventry CV4 7AL, UK. 4 Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville 37232 TN, USA. -
Decreased DNA Methylation at Promoters and Gene-Specific Neuronal
medRxiv preprint doi: https://doi.org/10.1101/2020.12.10.20246405; this version posted December 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder Miki Bundo1†, Junko Ueda1,2†, Yutaka Nakachi1, Kiyoto Kasai3,4, Tadafumi Kato2,5#, Kazuya Iwamoto1# 1Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Japan 2Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Japan 3Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Japan 4The International Research Center for Neurointelligence (WPI-IRCN) at The University of Tokyo Institutes for Advanced Study (UTIAS), 5Department of Psychiatry and Behavioral Science, Graduate School of Medicine, Juntendo University †contributed equally to this work #corresponding authors: Kazuya Iwamoto Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University. 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan [email protected] Tadadumi Kato Department of Psychiatry and Behavioral Science, Graduate School of Medicine, Juntendo University. 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan [email protected]. Running title: DNA methylation analysis in bipolar disorder 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.10.20246405; this version posted December 11, 2020. -
Activation of Intracellular Transport by Relieving KIF1C Autoinhibition
bioRxiv preprint doi: https://doi.org/10.1101/488049; this version posted December 6, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Activation of intracellular transport by relieving KIF1C autoinhibition Nida Siddiqui1,2, Alice Bachmann1,2, Alexander James Zwetsloot1,3, Hamdi Hussain1,2, Daniel Roth1,2, Irina Kaverina4 and Anne Straube1,2,* 1 Centre for Mechanochemical Cell Biology, University of Warwick, Coventry, CV4 7AL, UK 2 Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK 3 MRC-DTP in Interdisciplinary Biomedical Research, Warwick Medical School, Coventry, CV4 7AL, UK 4 Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville 37232, TN, USA * correspondence to [email protected]; +44 (0) 2476 151 169 Abstract The kinesin-3 KIF1C is a fast organelle transporter implicated in the transport of dense core vesicles in neurons and the delivery of integrins to cell adhesions. Here we report the mechanisms of autoinhibition and release that control the activity of KIF1C. We show that the microtubule binding surface of KIF1C motor domain interacts with its stalk and that these autoinhibitory interactions are released upon binding of protein tyrosine phosphatase PTPN21. The FERM domain of PTPN21 stimulates dense core vesicle transport in primary hippocampal neurons and rescues integrin trafficking in KIF1C-depleted cells. In vitro, human full-length KIF1C is a processive, plus-end directed motor. Its landing rate onto microtubules increases in the presence of either PTPN21 FERM domain or the cargo adapter Hook3 that binds the same region of KIF1C tail.