3e2u | pdb_00003e2u
Crystal structure of the zink-knuckle 2 domain of human CLIP-170 in complex with CAP-Gly domain of human dynactin-1 (p150-GLUED)
Structural highlights
DiseaseDCTN1_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] FunctionDCTN1_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 PubMedIn all eukaryotes, CAP-Gly proteins control important cellular processes. The molecular mechanisms underlying the functions of CAP-Gly domains, however, are still poorly understood. Here we use the complex formed between the CAP-Gly domain of p150(glued) and the C-terminal zinc knuckle of CLIP170 as a model system to explore the structure-function relationship of CAP-Gly-mediated protein interactions. We demonstrate that the conserved GKNDG motif of CAP-Gly domains is responsible for targeting to the C-terminal EEY/F sequence motifs of CLIP170, EB proteins and microtubules. The CAP-Gly-EEY/F interaction is essential for the recruitment of the dynactin complex by CLIP170 and for activation of CLIP170. Our findings define the molecular basis of CAP-Gly domain function, including the tubulin detyrosination-tyrosination cycle. They further establish fundamental roles for the interaction between CAP-Gly proteins and C-terminal EEY/F sequence motifs in regulating complex and dynamic cellular processes. Structure-function relationship of CAP-Gly domains.,Weisbrich A, Honnappa S, Jaussi R, Okhrimenko O, Frey D, Jelesarov I, Akhmanova A, Steinmetz MO Nat Struct Mol Biol. 2007 Oct;14(10):959-67. Epub 2007 Sep 9. PMID:17828277[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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