9b7j
From Proteopedia
Cryo-EM structure of human dynactin complex bound to Chlamydia effector Dre1
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. Publication Abstract from PubMedThe obligate intracellular pathogen Chlamydia trachomatis replicates in a specialized membrane-bound compartment where it repositions host organelles during infection to acquire nutrients and evade host surveillance. We describe a bacterial effector, Dre1, that binds specifically to dynactin associated with host microtubule organizing centers without globally impeding dynactin function. Dre1 is required to reposition the centrosome, mitotic spindle, Golgi apparatus, and primary cilia around the inclusion and contributes to pathogen fitness in cell-based and mouse models of infection. We utilized Dre1 to affinity purify the megadalton dynactin protein complex and determined the first cryoelectron microscopy (cryo-EM) structure of human dynactin. Our results suggest that Dre1 binds to the pointed end of dynactin and uncovers the first bacterial effector that modulates dynactin function. Our work highlights how a pathogen employs a single effector to evoke targeted, large-scale changes in host cell organization that facilitate pathogen growth without inhibiting host viability. The Chlamydia effector Dre1 binds dynactin to reposition host organelles during infection.,Sherry J, Pawar KI, Dolat L, Smith E, Chang IC, Pha K, Kaake R, Swaney DL, Herrera C, McMahon E, Bastidas RJ, Johnson JR, Valdivia RH, Krogan NJ, Elwell CA, Verba K, Engel JN Cell Rep. 2025 Apr 3;44(4):115509. doi: 10.1016/j.celrep.2025.115509. PMID:40186871[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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