Characterization of kinesin switch I mutations that cause hereditary spastic paraplegia

Kif5A is a neuronally-enriched isoform of the Kinesin-1 family of cellular transport motors. 23 separate mutations in the motor domain of Kif5A have been identified in patients with the complicated form of hereditary spastic paraplegia (HSP). We performed in vitro assays on dimeric recombinant Kif5A with HSP-causing mutations in the Switch I domain, which participates in the coordination and hydrolysis of ATP by kinesin. We observed a variety of significantly reduced catalytic and mechanical activities as a result of each mutation, with the shared phenotype from each that motility was significantly reduced. Substitution of Mn2+ for Mg2+ in our reaction buffers provides a dose-dependent rescue in both the catalytic and ensemble mechanical properties of the S203C mutant. This work provides mechanistic insight into the cause of HSP in patients with these mutations and points to future experiments to further dissect the root cause of this disease.

[1]  B. Gigant,et al.  The structural switch of nucleotide-free kinesin , 2017, Scientific Reports.

[2]  A. Tessa,et al.  Hereditary spastic paraplegia: Novel mutations and expansion of the phenotype variability in SPG56. , 2015, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[3]  V. Volpini,et al.  Identification of two novel KIF5A mutations in hereditary spastic paraplegia associated with mild peripheral neuropathy , 2015, Journal of the Neurological Sciences.

[4]  S. Klebe,et al.  Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting. , 2015, Revue neurologique.

[5]  A. Padovani,et al.  A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype. , 2015, Journal of clinical neuromuscular disease.

[6]  T. Kawarai,et al.  Hereditary spastic paraplegia : a novel mutation and expansion of the phenotype variability in SPG 10 , 2015 .

[7]  Marcel Knossow,et al.  The structure of apo-kinesin bound to tubulin links the nucleotide cycle to movement , 2014, Nature Communications.

[8]  R. Tortelli,et al.  A novel KIF5A mutation in an Italian family marked by spastic paraparesis and congenital deafness , 2014, Journal of the Neurological Sciences.

[9]  D. Hughes,et al.  Extended phenotypic spectrum of KIF5A mutations , 2014, Neurology.

[10]  A. Plückthun,et al.  Structure of a kinesin–tubulin complex and implications for kinesin motility , 2013, Nature Structural &Molecular Biology.

[11]  Tobias M. Rasse,et al.  Spastic Paraplegia Mutation N256S in the Neuronal Microtubule Motor KIF5A Disrupts Axonal Transport in a Drosophila HSP Model , 2012, PLoS genetics.

[12]  D. Rose,et al.  Three Routes to Suppression of the Neurodegenerative Phenotypes Caused by Kinesin Heavy Chain Mutations , 2012, Genetics.

[13]  N. Bresolin,et al.  Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot–Marie–Tooth type 2 , 2012, Clinical genetics.

[14]  J. Finsterer,et al.  Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance , 2012, Journal of Neurological Sciences.

[15]  F. Kull,et al.  A METAL SWITCH FOR CONTROLLING THE ACTIVITY OF MOLECULAR MOTOR PROTEINS , 2011, Nature Structural &Molecular Biology.

[16]  M. Grandis,et al.  A novel mutation in KIF5A gene causing hereditary spastic paraplegia with axonal neuropathy , 2011, Neurological Sciences.

[17]  R. Vale,et al.  Kinesin-73 Is a Processive Motor That Localizes to Rab5-containing Organelles* , 2010, The Journal of Biological Chemistry.

[18]  Sunyoung Kim,et al.  ATP Hydrolysis in Eg5 Kinesin Involves a Catalytic Two-water Mechanism*♦ , 2009, The Journal of Biological Chemistry.

[19]  J. Piccirilli,et al.  Identification of catalytic metal ion ligands in ribozymes. , 2009, Methods.

[20]  A. Durr,et al.  Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10 , 2009, Human mutation.

[21]  Arne Gennerich,et al.  Walking the walk: how kinesin and dynein coordinate their steps. , 2009, Current opinion in cell biology.

[22]  A. Federico,et al.  A novel KIF5A/SPG10 mutation in spastic paraplegia associated with axonal neuropathy , 2008, Journal of Neurology.

[23]  Rebecca Schüle,et al.  Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. , 2008, Human molecular genetics.

[24]  R. Schüle,et al.  SPG10 is a rare cause of spastic paraplegia in European families , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

[25]  M. Fichera,et al.  A missense mutation in the coiled-coil domain of the KIF5A gene and late-onset hereditary spastic paraplegia. , 2006, Archives of neurology.

[26]  P. Hedera,et al.  Mutation in KIF5A can also cause adult-onset hereditary spastic paraplegia , 2006, Neurogenetics.

[27]  M. Fichera,et al.  Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia , 2004, Neurology.

[28]  M. Castoldi,et al.  Purification of brain tubulin through two cycles of polymerization-depolymerization in a high-molarity buffer. , 2003, Protein expression and purification.

[29]  M. Pericak-Vance,et al.  A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). , 2002, American journal of human genetics.

[30]  F. Kull,et al.  Kinesin: switch I & II and the motor mechanism. , 2002, Journal of cell science.

[31]  S. Endow,et al.  A structural pathway for activation of the kinesin motor ATPase , 2001, The EMBO journal.

[32]  C. McDermott,et al.  Hereditary spastic paraparesis: a review of new developments , 2000, Journal of neurology, neurosurgery, and psychiatry.

[33]  F J Kull,et al.  Motor proteins of the kinesin family. Structures, variations, and nucleotide binding sites. , 1999, European journal of biochemistry.

[34]  Laxmikant V. Kale,et al.  NAMD2: Greater Scalability for Parallel Molecular Dynamics , 1999 .

[35]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[36]  Ronald D Vale,et al.  Microtubule Interaction Site of the Kinesin Motor , 1997, Cell.

[37]  R. Vale,et al.  Switches, latches, and amplifiers: common themes of G proteins and molecular motors , 1996, The Journal of cell biology.

[38]  Ronald D. Vale,et al.  Crystal structure of the kinesin motor domain reveals a structural similarity to myosin , 1996, Nature.

[39]  E. Taylor,et al.  Kinetic mechanism of kinesin motor domain. , 1995, Biochemistry.

[40]  Susan P. Gilbert,et al.  Pathway of processive ATP hydrolysis by kinesin , 1995, Nature.

[41]  R. P. Bruyn,et al.  The neuropathology of hereditary spastic paraparesis , 1992, Clinical Neurology and Neurosurgery.

[42]  E. Taylor,et al.  A kinetic study of the kinesin ATPase. , 1992, The Journal of biological chemistry.

[43]  D. Hackney,et al.  Kinesin ATPase: rate-limiting ADP release. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[44]  W. Behan,et al.  Strümpell's familial spastic paraplegia: genetics and neuropathology , 1974, Journal of neurology, neurosurgery, and psychiatry.