The encoded protein possesses unique mechanochemical properties used to tubulate and sever membranes, and is involved in clathrinmediated endocytosis and. Developmental defects and perinatal lethal syndromes are heterogeneous diseases caused by environmental andor genetic factors. Several mutant dynamin proteins that negatively impact membrane receptor. The expanded programme of immunization epi module 3. Inhibiting dynamin has proven a useful strategy to explore its contributions and mechanisms of action during cellular processes, particularly endocytosis. Dynamin 2 dnm2 belongs to a family of large gtpases that are well known for mediating membrane fission by oligomerizing at the neck of membrane invaginations.
Vertebrates express 3 isoforms of modernclassical dynamins ramachandran and schmid, 2018, namely dynamin 1, dynamin 2 and dynamin 3 dyn1, dyn2 and dyn3. The expression of dynamin 1, 2, and 3 in human hepatocellular carcinoma and patient prognosis. Zebrafish as a model to investigate dynamin 2related diseases. Dynamin is part of the dynamin superfamily, which includes classical dynamins, dynamin like proteins, mx proteins, opa, mitofusins, and gbps. Late treatment in the diseases time course partially improve the phenotype due to a weaker transduction capacity of the muscle. Molecular recognition in the infection, replication, and transmission of covid19causing sarscov 2. Dynamin2 is a ubiquitously expressed mechanogtpase involved in different.
Endogenous and myctag mtorc1 was purified, ingel tryptic digested and then identified by nanolc esi qtof msms analysis. Heterozygous individuals are predisposed to polycystic kidney disease because they are likely to. Slides were peroxidase blocked in 3% h2o2 in methanol for 10 mins. Dnm2 is a large gtpase mainly involved in membrane trafficking through its function in the formation and release of nascent vesicles from biological membranes. Fakmediated src phosphorylation of endophilin a2 inhibits endocytosis of mt1mmp and promotes ecm degradation. Most common disease related dynamin 2 mutations are represented. About frontiers institutional membership books news frontiers social. Dynamin2 function and dysfunction along the secretory. Biosafety in microbiological and biomedical laboratories.
Ebola virus enters host cells by macropinocytosis and. Members of the dynamin family are found throughout the eukaryotic kingdom. Nov 09, 2016 the isolated phd has very low affinity for anionic lipids, including pip 2 klein et al. Mitochondrial fission in human diseases springerlink. Pdf dynamin 2 mutations associated with human diseases. The present study was undertaken to identify proteins that interact with the mammalian target of rapamycin complex 1 mtorc1 to enable it to carry out its crucial cell signaling functions. The dnm2 gene provides instructions for making a protein called dynamin 2. Icd10 second edition volume 2 world health organization. Dynamics of dynaminrelated protein 1 in alzheimers disease. The tethering of mitochondria together is followed by gtp hydrolysis, which induces conformation changes to cause mitochondrial fusion. In silico identification of potential dynamin related protein 1 antagonists. The dynamin family includes dynamin 1 dnm1, dynamin 2 dnm2, and dynamin 3 dnm3, which are known as classic dynamins. A direct interaction between the large gtpase dynamin2.
Nov 20, 2017 rab35 mediates membrane trafficking between the plasma membrane and the early endosomes at the cell surface. Another example of a dynamin binding partner is actinbinding protein 1 abp1, which binds to human dynamin 2 through its sh3 domains and to factin through its actinbinding domains. To our surprise, we found that viral infections are suppressed by bisphosphonates by inhibiting the gtpase activity of dynamin. Dynamin domain organization, dnm2 disease mutations, and its. Our understanding of the cellular function of rab35 reveals its role in development and diseases. Infections spread by animals and insects and less common infectious diseases module 5. Defective membrane remodeling in neuromuscular diseases. The bad bug book chapters about pathogenic bacteria are divided into two main groups, based on the structure of the microbes cell wall. Muscle is a unique tissue with elaborated membrane and cytoskeleton organization designed for excitationcontraction coupling and force generation.
Dynamin 2 is a 100 kda multidomain protein and a member of the dynamin superfamily, which consists of three classical dynamins and dynamin related proteins 1415. Crystal structure of nucleotidefree dynamin nature. Vessels were then incubated under culture conditions for 24 h before vasoactivity testing under either ng or lg conditions 2 h exposure. Increased dynamin expression precedes proteinuria in glomerular. Src kinase regulates the integrity and function of the golgi apparatus via activation of dynamin 2 proc natl acad sci usa 107 58635868. Dynamin 2 dnm2 mutations cause autosomal dominant centronuclear. The function of rab35 in development and disease intechopen. Dynamin 2 is a ubiquitously expressed mechanogtpase involved in different. For human arterioles, the lipofectaminernai mixture was passed through the lumen of the vessel and allowed to remain within the lumen for 46 h before washout at a low flow rate shear stress 2.
Dynamin 2 dnm2 as cause of, and modifier for, human. Dynamin and endocytosis are required for the fusion of. The pleckstrinhomology domain of dynamin is dispensable for. Dynamin 1 is phosphorylated at synapses where sve is activated by its rapid dephosphorylation. Dynamin 1 is a protein that in humans is encoded by the dnm1 gene. Thats why its so vital to take action to prevent this disease. At least four splice variants of each of the three dynamins have been isolated in human tissue. Rich agriculture handbook no, 474 slightly revised december 1979 washington, d. Charcotmarietooth disease is classified in two main groups on the basis of electrophysiologic. C, issued october 1976 for sale by the superintendent of documents, u. Many human myopathies are caused by mutations of proteins responsible for membrane trafficking, and one of them is the critical regulator of clathrinmediated endocytosis cme, dynamin 2 dyn2 2, 3. Mutations in dynamin ii have been found to cause dominant intermediate charcotmarietooth disease. Mitochondria are the center of metabolism and the critical role of aberrant mitochondrial fission in the onset and progression of a wide range of human diseases such as neurodegenerative disorders, cardiovascular disease, ischemic stroke and diabetes, is slowly becoming recognized. In this chapter we examine the recent literature on the mitochondrial dynamicsfunction relationship, and explore how it impacts on the development and.
Dynaminrelated protein 1 mediates low glucoseinduced. Dynamin 2 is correlated with recurrence and poor prognosis of papillary thyroid cancer. If these mutations occur in the stalk domain, they yield abnormally stable. The supply of svs is controlled by dynamin dependent endocytosis, which is a ratelimiting step for synaptic transmission. The importance of vitamin c in preventing cancer and cardiovascular disease, its relevance to aging and stress, and its impacts on each of the human body systems are thoroughly assessed on the basis of the authors extensive research and his deep understanding, as an anatomy professor, of the body as a whole. Insights into dynaminassociated disorders through analysis of. An increasing number of mutations in the human classical dynamins, dyn1 and dyn 2 has been reported, with diseases caused by these. Intrapolypeptide interactions between the gtpase effector. Dynamin is a 100kda protein macromolecule, belonging to the superfamily of gtpases, which plays a major role in synaptic vesicle transport. While several proteins from these different families are implicated in similar diseases, mutations in close homologues or in the same protein in the case of dynamin 2 lead to diseases affecting different tissues.
Dynamin 2 dnm2 mutations cause autosomal dominant centronuclear myopathy, a rare form of congenital myopathy, and intermediate and axonal forms of charcotmarietooth disease, a peripheral neuropathy. Heart disease is a serious disease and too often, a fatal one. These proteins are involved in the remodeling and trafficking of cell membranes, and pathological studies show dysfunction in the sarcotubular system in cnm. Here we report that ebola cytotoxicity involves a cellular trafficking pathway that is dependent upon dynamin, a gtpase that mediates transport vesicle formation. The purpose of this article is to highlight the role of dynamin related protein 1 drp1 in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagymitophagy, and neuronal damage in alzheimers disease ad and other neurological diseases, including parkinsons, huntingtons, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and obesity. Dynamin 2 nprap colocalization and direct interaction in vivo, was investigated. Sep 18, 2011 the structure was solved by molecular replacement, using the nucleotidefree rat dynamin 1 gtpase domain, the human dynamin 1 ph and a portion of the human mxa stalk, as sequential search models. The mitofusins are transmembrane dynamin related gtpases, which induce the joining of 2 mitochondrial fragments by forming dimers across the interface.
Dnm2 mice progressively develop features of the human cnm including. On the basis of clinical presentation, it is possible to discern two basic types of disease phenotypes. Dynamin2 is a protein that in humans is encoded by the dnm2 gene. In the developmental context, rab35 has been shown to play an important role in regulating epithelial polarity, lumen opening, myoblast fusion, intercalation of epithelium, myelination. In silico identification of potential dynaminrelated. Many cell types seem to be susceptible to ebov infection, but lymphocytes are known to be resistant 2, 3. By linking the actin cytoskeleton and endocytic proteins, abp1 is thought to initiate the internalization of bcell receptors, thereby regulating antigen. Aug 24, 2015 r518 in dynamin 3 corresponds to r522 in dynamin 2 and the r522h mutation in dynamin 2 is implicated in centronuclear myopathy.
Genetic analysis revealed that mutations in human dynamin 2 were connected with defects in endocytosis. Chronic kidney disease ckd is a major health issue. The dnm2 gene located on human chromosome 19 encodes for dynamin 2, a ubiquitously expressed protein. Fourth edition anthrax who world health organization. A new study shows that mutations in the gene encoding dynamin 2 underlie a distinct form of peripheral neuropathy, establishing the first link between dynamins and human disease. Dynamin 2 dnm2 mutations cause autosomal dominant centronuclear myopathy, a rare form of congenital myopathy, and intermediate and axonal. Here we show that ebola viruslike particles ebovvlps composed of the glycoprotein gp 1, 2 and the matrix protein vp40 use macropinocytosis and clathrinmediated endocytosis to enter cells. Pierson, in pathobiology of human disease, 2014 recent research. James nelson, in physiology of the gastrointestinal tract fourth edition, 2006. The mild functional defects are suggestive of differences between cmt and cnm disease causing dynamin 2 mutants and suggest that a slight impairment in clathrinmediated pathways may accumulate over time to foster the respective human diseases. Indeed, preliminary studies showed that deletion of dynamin 1 alone had only mild effects on these cells. Dynamic instability of microtubules requires dynamin 2 and.
The dynamin superfamily of proteins is characterized by the presence of three conserved core domains. The three classical dynamins expressed in mammals are the neuronspecific dynamin 1 mim 602377 shpetner and vallee, 1989, the ubiquitously expressed dynamin 2 mim 602378 cook et al. There are several dynamin related diseases, and dynamin inhibitors may have therapeutic utility. The clinical assessment, treatment and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis. Dynamin2 mutations associated with centronuclear myopathy. Members of the dynamin family are principally involved in the scission of newly formed vesicles from the membrane of one cellular compartment and their targeting to, and fusion with. Parkinsons disease, huntingtons disease, charcotmarietooth disease, heart failure, schizophrenia, epilepsy, cancer, dominant. In addition to centronuclear myopathy, dynamin 2 is also mutated in a dominant form of charcotmarietooth neuropathy. Many others with heart problems become permanently disabled.
Request pdf dynamin 2 mutations associated with human diseases impair clathrinmediated receptor endocytosis dynamin 2 dnm2 is a large gtpase involved in the release of nascent vesicles. May 10, 2004 disease description an axonal form of charcotmarietooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Centers for disease control and prevention byron caughey, phd. A novel mutation in the dynamin 2 gene in a charcotmarietooth type 2 patient.
A total of nine novel interacting proteins were identified in both endogenous and. Dynamin 2 is a protein that in humans is encoded by the dnm2 gene. Dynamin 2 mutations associated with human diseases impair. Infections spread by sexual contact and blood and body fluids. Autosomal dominant mutations in the ubiquitously expressed dnm2 cause 2 discrete neuromuscular diseases. The dynamins 1, 2, and 3 are part of a large superfamily of gtpases that function in membrane tubulation and scission. Sporadic centronuclear myopathy with muscle pseudohypertrophy.
A direct interaction between the large gtpase dynamin2 and. Sections were rehydrated and antigen retrieved with the dako 3 in 1 ar buffers edta ph 9. Dynamin was the first protein shown to be directly involved in membrane fission koenig et al. Dynamin 2 homozygous mutation in humans with a lethal congenital. Virus entry into host cells is the first step of infection and a crucial determinant of pathogenicity. Dnm2 dyn2 dnm2 by interspecific backcross analysis, klocke et al. This gene encodes a member of the dynamin subfamily of gtpbinding proteins. Dynamin 2 mutations associated with human diseases impair clathrinmediated receptor endocytosis. An increasing number of mutations in the human classical dynamins, dyn1 and dyn2 has been reported, with diseases caused by these. Vitamin c in human health and disease springerlink.
The structure reveals dynamin s catalytic machinery and explains how assemblystimulated gtp hydrolysis is achieved through g domain dimerization. Senior investigator laboratory of persistent viral diseases, rocky mountain laboratories national institute for allergy and infectious diseases national institutes of health rear admiral terri r. According to the lately survey, dynamin 3 is lowexpressed in tumor tissue samples and cell lines of human cancers. Pmc, all databases, assembly, biocollections, bioproject, biosample, biosystems, books, clinvar, conserved domains. For example, excessive mitochondrial division fission is associated with functional defects, and is implicated in multiple human diseases from neurodegenerative diseases to cancer. School of biotechnology, coordinator, dbt bioinformatics center, national institute of technology calicut, calicut 673601, india. Parkinsons disease, huntingtons disease, charcotmarietooth. The pleckstrinhomology domain of dynamin is dispensable. It is the number one killer of americans, with 500,000 people in the united states dying of heart disease each year. Dynamin i is expressed in neurons and neuroendocrine cells.
Disease mutations in either polycystin1 pkd1 or polycystin 2 pkd2 gene autosomal dominant disease appears to follow a twohit model, requiring the loss of both alleles of pdk1 or pdk2 for the disease to be evident. Dnm2 and bin1 encode dynamin 2 and amphiphysin 2, respectively. Most common diseaserelated dynamin2 mutations are represented. In silico identification of potential dynaminrelated protein. Dynamin iii is strongly expressed in the testis, but is also present in heart, brain, and lung tissue. Expression of dynamin 3 in various diseases table 1 booken n 11 confirmed that dynamin 3 is.
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