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Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences.

ABSTRACT: The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically disordered and involved in multiple molecular interactions important for normal physiology and pathology of chronic neurodegenerative diseases. Nuclear magnetic resonance and cryo-electron microscopy recently revealed propensities of MAPs to form transient local structures and long-range contacts in the free state, and conformations adopted in complexes with microtubules and filamentous actin, as well as in pathological aggregates. In this paper, we compare the longest, 441-residue brain isoform of tau (tau40), and a 467-residue isoform of MAP2, known as MAP2c. For both molecules, we present transient structural motifs revealed by conformational analysis of experimental data obtained for free soluble forms of the proteins. We show that many of the short sequence motifs that exhibit transient structural features are linked to functional properties, manifested by specific interactions. The transient structural motifs can be therefore classified as molecular recognition elements of tau40 and MAP2c. Their interactions are further regulated by post-translational modifications, in particular phosphorylation. The structure-function analysis also explains differences between biological activities of tau40 and MAP2c.

SUBMITTER: Melkova K

PROVIDER: S-EPMC6468450 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences.

Melková Kateřina K Zapletal Vojtěch V Narasimhan Subhash S Jansen Séverine S Hritz Jozef J Škrabana Rostislav R Zweckstetter Markus M Ringkjøbing Jensen Malene M Blackledge Martin M Žídek Lukáš L

Biomolecules 20190316 3

The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically disordered and involved in multiple molecular interactions important for normal physiology and pathology of chronic neurodegenerative diseases. Nuclear magnetic resonance and cryo-electron microscopy recently revealed propensities of MAPs to form transient local structures and long-range contacts in the free state, and conformation ...[more]

PMID: 30884818

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Project description:BackgroundTauopathies represent a diverse group of neurodegenerative disorders characterized by the abnormal aggregation of the microtubule-associated protein tau. Despite extensive research, the mechanisms underlying the diversity of neuronal and glial tau pathology in different tauopathies are poorly understood. While there is a growing understanding of tauopathy-specific differences in tau isoforms and fibrillar structures, the specific composition of heterogenous tau lesions remains unknown. Here we study the protein composition of tau aggregates in four major tauopathies: Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's disease (PiD), and progressive supranuclear palsy (PSP).MethodsWe developed an approach for in situ proximity labeling and isolation of aggregate-associated proteins using glass slides with formalin-fixed paraffin-embedded (FFPE) human postmortem brain tissue, termed Probe-dependent Proximity Profiling (ProPPr). We used ProPPr for the analysis of proteomes associated with AT8-positive cellular lesions from frontal cortices. Isolated proximity proteomes were analyzed by data-independent acquisition mass spectrometry. Co-immunofluorescence staining and quantitative data analysis for selected proteins in human brain tissue was performed to further investigate associations with diverse tau pathologies.ResultsProteomics data analysis identified numerous common and tauopathy-specific proteins associated with phospho-tau aggregates. Extensive validations of candidates through quantitative immunofluorescence imaging of distinct aggregates across disease cases demonstrate successful implementation of ProPPr for unbiased discovery of aggregate-associated proteins in in human brain tissue. Our results reveal the association of retromer complex component vacuolar protein sorting-associated protein 35 (VPS35) and lysosome-associated membrane glycoprotein 2 (LAMP2) with specific types of phospho-tau lesions in tauopathies. Furthermore, we discovered a disease-specific association of certain proteins with distinct pathological lesions, including glycogen synthase kinase alpha (GSK3α), ferritin light chain (FTL), and the neuropeptide precursor VGF. Notably, the identification of FTL-positive microglia in CBD astrocytic plaques indicate their potential role in the pathogenesis of these lesions.ConclusionsOur findings demonstrate the suitability of the ProPPr approach in FFPE brain tissue for unbiased discovery of local proteomes that provide valuable insights into the underlying proteomic landscape of tauopathies, shedding light on the molecular mechanisms underlying tau pathology. This first comprehensive characterization of tau-associated proteomes in a range of distinct tauopathies enhances our understanding of disease heterogeneity and mechanisms, informing strategies for the development of diagnostic biomarkers and targeted therapies.

Dataset Information

Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences.

Publications

Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences.

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