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2hkq

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Crystal structure of the C-terminal domain of human EB1 in complex with the CAP-Gly domain of human Dynactin-1 (p150-Glued)Crystal structure of the C-terminal domain of human EB1 in complex with the CAP-Gly domain of human Dynactin-1 (p150-Glued)

Structural highlights

2hkq is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:MAPRE1 (HUMAN), DCTN1 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[DCTN1_HUMAN] Defects in DCTN1 are the cause of distal hereditary motor neuronopathy type 7B (HMN7B) [MIM:607641]; also known as progressive lower motor neuron disease (PLMND). HMN7B is a neuromuscular disorder. Distal hereditary motor neuronopathies constitute a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs.[1] [2] [3] [4] Defects in DCTN1 are a cause of susceptibility to amyotrophic lateral sclerosis (ALS) [MIM:105400]. ALS is a neurodegenerative disorder affecting upper and lower motor neurons, and resulting in fatal paralysis. Sensory abnormalities are absent. Death usually occurs within 2 to 5 years. The etiology is likely to be multifactorial, involving both genetic and environmental factors.[5] [6] Defects in DCTN1 are the cause of Perry syndrome (PERRYS) [MIM:168605]; also called parkinsonism with alveolar hypoventilation and mental depression. Perry syndrome is a neuropsychiatric disorder characterized by mental depression not responsive to antidepressant drugs or electroconvulsive therapy, sleep disturbances, exhaustion and marked weight loss. Parkinsonism develops later and respiratory failure occurred terminally.[7]

Function

[MARE1_HUMAN] Binds to the plus end of microtubules and regulates the dynamics of the microtubule cytoskeleton. Promotes cytoplasmic microtubule nucleation and elongation. May be involved in spindle function by stabilizing microtubules and anchoring them at centrosomes. May play a role in cell migration.[8] [9] [10] [11] [DCTN1_HUMAN] Required for the cytoplasmic dynein-driven retrograde movement of vesicles and organelles along microtubules. Dynein-dynactin interaction is a key component of the mechanism of axonal transport of vesicles and organelles.

Evolutionary Conservation

 

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Dynamic microtubule plus-end tracking protein (+TIP) networks are implicated in all functions of microtubules, but the molecular determinants of their interactions are largely unknown. Here, we have explored key binding modes of +TIPs by analyzing the interactions between selected CAP-Gly, EB-like, and carboxy-terminal EEY/F-COO(-) sequence motifs. X-ray crystallography and biophysical binding studies demonstrate that the beta2-beta3 loop of CAP-Gly domains determines EB-like motif binding specificity. They further show how CAP-Gly domains serve as recognition domains for EEY/F-COO(-) motifs, which represent characteristic and functionally important sequence elements in EB, CLIP-170, and alpha-tubulin. Our findings provide a molecular basis for understanding the modular interaction modes between alpha-tubulin, CLIPs, EB proteins, and the dynactin-dynein motor complex and suggest that multiple low-affinity binding sites in different combinations control dynamic +TIP networks at microtubule ends. They further offer insights into the structural consequences of genetic CAP-Gly domain defects found in severe human disorders.

Key interaction modes of dynamic +TIP networks.,Honnappa S, Okhrimenko O, Jaussi R, Jawhari H, Jelesarov I, Winkler FK, Steinmetz MO Mol Cell. 2006 Sep 1;23(5):663-71. PMID:16949363[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, Brown RH Jr, Ludlow CL, Fischbeck KH. Mutant dynactin in motor neuron disease. Nat Genet. 2003 Apr;33(4):455-6. Epub 2003 Mar 10. PMID:12627231 doi:10.1038/ng1123
  2. ↑ Levy JR, Sumner CJ, Caviston JP, Tokito MK, Ranganathan S, Ligon LA, Wallace KE, LaMonte BH, Harmison GG, Puls I, Fischbeck KH, Holzbaur EL. A motor neuron disease-associated mutation in p150Glued perturbs dynactin function and induces protein aggregation. J Cell Biol. 2006 Feb 27;172(5):733-45. PMID:16505168 doi:10.1083/jcb.200511068
  3. ↑ Farrer MJ, Hulihan MM, Kachergus JM, Dachsel JC, Stoessl AJ, Grantier LL, Calne S, Calne DB, Lechevalier B, Chapon F, Tsuboi Y, Yamada T, Gutmann L, Elibol B, Bhatia KP, Wider C, Vilarino-Guell C, Ross OA, Brown LA, Castanedes-Casey M, Dickson DW, Wszolek ZK. DCTN1 mutations in Perry syndrome. Nat Genet. 2009 Feb;41(2):163-5. doi: 10.1038/ng.293. Epub 2009 Jan 11. PMID:19136952 doi:10.1038/ng.293
  4. ↑ Moore JK, Sept D, Cooper JA. Neurodegeneration mutations in dynactin impair dynein-dependent nuclear migration. Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5147-52. doi:, 10.1073/pnas.0810828106. Epub 2009 Mar 11. PMID:19279216 doi:10.1073/pnas.0810828106
  5. ↑ Munch C, Sedlmeier R, Meyer T, Homberg V, Sperfeld AD, Kurt A, Prudlo J, Peraus G, Hanemann CO, Stumm G, Ludolph AC. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology. 2004 Aug 24;63(4):724-6. PMID:15326253
  6. ↑ Munch C, Rosenbohm A, Sperfeld AD, Uttner I, Reske S, Krause BJ, Sedlmeier R, Meyer T, Hanemann CO, Stumm G, Ludolph AC. Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and FTD. Ann Neurol. 2005 Nov;58(5):777-80. PMID:16240349 doi:10.1002/ana.20631
  7. ↑ Farrer MJ, Hulihan MM, Kachergus JM, Dachsel JC, Stoessl AJ, Grantier LL, Calne S, Calne DB, Lechevalier B, Chapon F, Tsuboi Y, Yamada T, Gutmann L, Elibol B, Bhatia KP, Wider C, Vilarino-Guell C, Ross OA, Brown LA, Castanedes-Casey M, Dickson DW, Wszolek ZK. DCTN1 mutations in Perry syndrome. Nat Genet. 2009 Feb;41(2):163-5. doi: 10.1038/ng.293. Epub 2009 Jan 11. PMID:19136952 doi:10.1038/ng.293
  8. ↑ Askham JM, Vaughan KT, Goodson HV, Morrison EE. Evidence that an interaction between EB1 and p150(Glued) is required for the formation and maintenance of a radial microtubule array anchored at the centrosome. Mol Biol Cell. 2002 Oct;13(10):3627-45. PMID:12388762 doi:10.1091/mbc.E02-01-0061
  9. ↑ van der Vaart B, Manatschal C, Grigoriev I, Olieric V, Gouveia SM, Bjelic S, Demmers J, Vorobjev I, Hoogenraad CC, Steinmetz MO, Akhmanova A. SLAIN2 links microtubule plus end-tracking proteins and controls microtubule growth in interphase. J Cell Biol. 2011 Jun 13;193(6):1083-99. Epub 2011 Jun 6. PMID:21646404 doi:10.1083/jcb.201012179
  10. ↑ Hayashi I, Wilde A, Mal TK, Ikura M. Structural basis for the activation of microtubule assembly by the EB1 and p150Glued complex. Mol Cell. 2005 Aug 19;19(4):449-60. PMID:16109370 doi:10.1016/j.molcel.2005.06.034
  11. ↑ Honnappa S, Gouveia SM, Weisbrich A, Damberger FF, Bhavesh NS, Jawhari H, Grigoriev I, van Rijssel FJ, Buey RM, Lawera A, Jelesarov I, Winkler FK, Wuthrich K, Akhmanova A, Steinmetz MO. An EB1-binding motif acts as a microtubule tip localization signal. Cell. 2009 Jul 23;138(2):366-76. PMID:19632184 doi:S0092-8674(09)00638-2
  12. ↑ Honnappa S, Okhrimenko O, Jaussi R, Jawhari H, Jelesarov I, Winkler FK, Steinmetz MO. Key interaction modes of dynamic +TIP networks. Mol Cell. 2006 Sep 1;23(5):663-71. PMID:16949363 doi:10.1016/j.molcel.2006.07.013

2hkq, resolution 1.86Å

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