MAP6 | |||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | MAP6 , MTAP6, N-STOP, STOP, MAP6-N, microtubule associated protein 6 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 601783 MGI: 1201690 HomoloGene: 7850 GeneCards: MAP6 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
|
Microtubule-associated protein 6 (MAP6) or stable tubule-only polypeptide (STOP or STOP protein) is a protein that in humans is encoded by the MAP6 gene. [5] [6]
This gene encodes a microtubule-associated protein (MAP). The encoded protein is a calmodulin binding, and calmodulin-regulated protein that is involved in microtubule stabilization.
MAP6 localization is present throughout neuronal maturation and axonal development. [7] It protects microtubules under drug and cold induced depolymerization by reducing the shrinking rate and promoting rescue events. A deficit in MAP6 protein levels is characterized by behavioral impairments, most notably schizophrenia.
A murine isoform of MAP6, MAP6-N, has 3 major domains:
12 calmodulin binding domains, 3 Mn domains, and 3-6 Mc domains. [8]
MAP6 can also associate with the Golgi apparatus through palmitoylation of their N-terminal domains. [9] N-terminal cysteines of MAP6 domain-containing protein 1 (MAP6d1), a postnatally expressed isoform in the mouse central nervous system, are palmitoylated by DHHC-type palmitoylating enzymes. Through palmitoylation, MAP6 can be targeted to a newly formed axon and is involved in microtubule and membrane shuttling.
MAP6 is a multi-functional protein. While it is involved with microtubules, it can also be involved in neuroreceptor homeostasis, endocytosis, nuclear function, and signal transduction pathways.
MAP6 interacts with microtubules by localizing in the lumen of microtubules. MAP6 alters the conformation of a growing microtubules by inducing the microtubule to coil into a left-handed helix with a long-range helicity with a pitch of 5.5 ± 0.8 μm. [10] This coiling pattern requires the Mn and Mc modules, as well as the first 35 N-terminal residues. MAP6 is also shown to be involved at the tip of the microtubule. Additionally, during microtubule polymerization, MAP6 induces the formation of stable apertures in the lattice, which is likely used to relieve mechanical stress.
In neuroreceptor homeostasis, MAP6 was consistently identified in synaptic proteomes, even though microtubules are only transiently present in both pre- and post-synaptic compartments of axonal boutons or dendritic spines. This suggests that MAP6 has microtubule independent roles as well. MAP6 is also associated with subicular neurons from the hippocampus, where it is involved with the receptors Neuropilin1, Plexin D1, and VEGFR2—which together make up the tripartite Semaphorin 3E receptor, which aids in the formation of the fornix. A knockout of the MAP6 gene in mice led to the absence of the post-commissural part of the fornix, producing a disconnect between the hippocampus and the hypothalamus. [11]
MAP6 is also involved in the olfactory bulb and the hippocampus, two regions where adult neurogenesis is known to occur. In neurogenesis studies with mice with the MAP6 knockout, there was an increase in the number of proliferating cells in the olfactory epithelium with increased apoptosis, [12] while there was a decrease in proliferating cells in the hippocampus. [13] The exact mechanism behind how MAP6 aids in neurogenesis is unclear.
A MAP6-related protein, TbSAXO, has been discovered in Trypanosoma brucei. [14] The domains of the protein responsible for microtubule binding and stabilizing share homologies with the Mn domains of MAP6.TbSAXO is an axonemal protein that plays a role in flagellum motility, showing that a MAP6-related protein can play a role in flagellum motility as well.
MAP6 functions as a neuronal protein that aids in microtubule stabilization. Studies with mice that have knockouts of MAP6 (MAP6 KO mice) are viable, but they show biological and behavioral alterations, which are similar to symptoms of schizophrenia.
MAP6 KO mice show hyperactivity, fragmentation of normal activity, anxiety-like behavior, social withdrawal, and impaired maternal behavior leading to the death of pups. [5] These symptoms correspond to changes in synaptic plasticity, which lead to large alterations in synaptic responses.The symptoms of the MAP6 KO mice are mainly treated by antipsychotic drugs or Epothilone D (Epo D), a microtubule-stabilizing molecule, which has also been shown to alleviate the synaptic plasticity defects in MAP6 KO mice. [15] Therefore, MAP6 KO mice serve as useful models for the treatment and pathophysiology of schizophrenia. In addition to schizophrenia, MAP6 KO mice also display a reduced volume of the cerebellum and the thalamus. Moreover, the mice had other brain anomalies, characterized by an altered size, integrity and spatial orientation of some neuronal tracks such as the anterior commissure, the mammillary tract, the corpus callosum, the corticospinal tract, the fasciculus retroflexus and the fornix. [16]
In a study conducted with the plasmas of children displaying classic-onset autism, the concentration of MAP6 protein levels were lower than that of healthy children. [17] In MAP6 KO mice conducted in the same study, there was a reduction in pre-synaptic glutamate vesicle density. Low glutamate release levels are common in autism, which could explain the reduced expression of the MAP6 protein. Another hypothesis is that less MAP6 can impair the myelin development in oligodendrocytes, which can lead to abnormalities in synaptic function and myelination that could explain the behavioral phenotypes in autism. [17]
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the binding of Ca2+ is required for the activation of calmodulin. Once bound to Ca2+, calmodulin acts as part of a calcium signal transduction pathway by modifying its interactions with various target proteins such as kinases or phosphatases.
CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.
The tau proteins are a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.
Calmodulin-binding proteins are, as their name implies, proteins which bind calmodulin. Calmodulin can bind to a variety of proteins through a two-step binding mechanism, namely "conformational and mutually induced fit", where typically two domains of calmodulin wrap around an emerging helical calmodulin binding domain from the target protein.
Ca2+
/calmodulin-dependent protein kinase II is a serine/threonine-specific protein kinase that is regulated by the Ca2+
/calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. CaMKII is also necessary for Ca2+
homeostasis and reuptake in cardiomyocytes, chloride transport in epithelia, positive T-cell selection, and CD8 T-cell activation.
Neurexins (NRXN) are a family of presynaptic cell adhesion proteins that have roles in connecting neurons at the synapse. They are located mostly on the presynaptic membrane and contain a single transmembrane domain. The extracellular domain interacts with proteins in the synaptic cleft, most notably neuroligin, while the intracellular cytoplasmic portion interacts with proteins associated with exocytosis. Neurexin and neuroligin "shake hands," resulting in the connection between the two neurons and the production of a synapse. Neurexins mediate signaling across the synapse, and influence the properties of neural networks by synapse specificity. Neurexins were discovered as receptors for α-latrotoxin, a vertebrate-specific toxin in black widow spider venom that binds to presynaptic receptors and induces massive neurotransmitter release. In humans, alterations in genes encoding neurexins are implicated in autism and other cognitive diseases, such as Tourette syndrome and schizophrenia.
PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene.
Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMKIIα), a.k.a.Ca2+/calmodulin-dependent protein kinase II alpha, is one subunit of CamKII, a protein kinase (i.e., an enzyme which phosphorylates proteins) that in humans is encoded by the CAMK2A gene.
Microtubule-associated protein 2 is a protein in humans that is encoded by the MAP2 gene.
Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene. This gene is also known by several other names: CMG 2, calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2. CASK gene mutations are the cause of XL-ID with or without nystagmus and MICPCH, an X-linked neurological disorder.
Microtubule-associated protein 4 is a protein that in humans is encoded by the MAP4 gene.
Calcium/calmodulin-dependent protein kinase type IV is an enzyme that in humans is encoded by the CAMK4 gene.
Tubulin alpha-1A chain is a protein that in humans is encoded by the TUBA1A gene.
Calcium/calmodulin-dependent protein kinase type 1 is an enzyme that in humans is encoded by the CAMK1 gene.
Myosin X, also known as MYO10, is a protein that in humans is encoded by the MYO10 gene.
Activity-regulated cytoskeleton-associated protein is a plasticity protein that in humans is encoded by the ARC gene. It was first characterized in 1995. ARC is a member of the immediate-early gene (IEG) family, a rapidly activated class of genes functionally defined by their ability to be transcribed in the presence of protein synthesis inhibitors. ARC mRNA is localized to activated synaptic sites in an NMDA receptor-dependent manner, where the newly translated protein is believed to play a critical role in learning and memory-related molecular processes. Arc protein is widely considered to be important in neurobiology because of its activity regulation, localization, and utility as a marker for plastic changes in the brain. Dysfunction in the production of Arc protein has been implicated as an important factor in understanding various neurological conditions, including amnesia, Alzheimer's disease, Autism spectrum disorders, and Fragile X syndrome. Along with other IEGs such as ZNF268 and HOMER1, ARC is also a significant tool for systems neuroscience as illustrated by the development of the cellular compartment analysis of temporal activity by fluorescence in situ hybridization, or catFISH technique.
Synapsin I, is the collective name for Synapsin Ia and Synapsin Ib, two nearly identical phosphoproteins that in humans are encoded by the SYN1 gene. In its phosphorylated form, Synapsin I may also be referred to as phosphosynaspin I. Synapsin I is the first of the proteins in the synapsin family of phosphoproteins in the synaptic vesicles present in the central and peripheral nervous systems. Synapsin Ia and Ib are close in length and almost the same in make up, however, Synapsin Ib stops short of the last segment of the C-terminal in the amino acid sequence found in Synapsin Ia.
Kinesin-like protein KIF1A, also known as axonal transporter of synaptic vesicles or microtubule-based motor KIF1A, is a protein that in humans is encoded by the KIF1A gene.
GCaMP is a genetically encoded calcium indicator (GECI) initially developed in 2001 by Junichi Nakai. It is a synthetic fusion of green fluorescent protein (GFP), calmodulin (CaM), and M13, a peptide sequence from myosin light-chain kinase. When bound to Ca2+, GCaMP fluoresces green with a peak excitation wavelength of 480 nm and a peak emission wavelength of 510 nm. It is used in biological research to measure intracellular Ca2+ levels both in vitro and in vivo using virally transfected or transgenic cell and animal lines. The genetic sequence encoding GCaMP can be inserted under the control of promoters exclusive to certain cell types, allowing for cell-type specific expression of GCaMP. Since Ca2+ is a second messenger that contributes to many cellular mechanisms and signaling pathways, GCaMP allows researchers to quantify the activity of Ca2+-based mechanisms and study the role of Ca2+ ions in biological processes of interest.
Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased expression of cytoskeletal and extracellular matrix elements and postsynaptic scaffold proteins, while pruning less active ones. For example, cell adhesion molecules (CAMs) play a large role in synaptic maintenance and stabilization. Gerald Edelman discovered CAMs and studied their function during development, which showed CAMs are required for cell migration and the formation of the entire nervous system. In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to learning and memory.