MANINDRA Bera

Verified email at yale.edu

Postdoctoral Associate, Department of Cell Biology
Yale School of Medicine



                                   

https://researchid.co/manindra.bera

RESEARCH INTERESTS

Biophysics, Biochemistry, Neuroscience, Membrane Biology, Nuclear Biology, Mechanotransduction, Biomechanics

9

Scopus Publications

115

Scholar Citations

6

Scholar h-index

5

Scholar i10-index

Scopus Publications

  • Molecular determinants of complexin clamping and activation function
    Manindra Bera, Sathish Ramakrishnan, Jeff Coleman, Shyam S Krishnakumar, and James E Rothman

    eLife, eISSN: 2050084X, Published: 20 April 2022 eLife Sciences Publications, Ltd
    Previously we reported that Synaptotagmin-1 and Complexin synergistically clamp the SNARE assembly process to generate and maintain a pool of docked vesicles that fuse rapidly and synchronously upon Ca2+ influx (Ramakrishnan et al., 2020). Here, using the same in vitro single-vesicle fusion assay, we determine the molecular details of the Complexin-mediated fusion clamp and its role in Ca2+-activation. We find that a delay in fusion kinetics, likely imparted by Synaptotagmin-1, is needed for Complexin to block fusion. Systematic truncation/mutational analyses reveal that continuous alpha-helical accessory-central domains of Complexin are essential for its inhibitory function and specific interaction of the accessory helix with the SNAREpins enhances this functionality. The C-terminal domain promotes clamping by locally elevating Complexin concentration through interactions with the membrane. Independent of their clamping functions, the accessory-central helical domains of Complexin also contribute to rapid Ca2+-synchronized vesicle release by increasing the probability of fusion from the clamped state.

  • Pulling the springs of a cell by single-molecule force spectroscopy
    Chandrayee Mukherjee, Manindra Bera, Sri Rama Koti Ainavarapu, and Kaushik Sengupta

    Emerging Topics in Life Sciences, ISSN: 23978554, eISSN: 23978562, Pages: 77-87, Published: May 2021 Portland Press Ltd.
    The fundamental unit of the human body comprises of the cells which remain embedded in a fibrillar network of extracellular matrix proteins which in turn provides necessary anchorage the cells. Tissue repair, regeneration and reprogramming predominantly involve a traction force mediated signalling originating in the ECM and travelling deep into the cell including the nucleus via circuitry of spring-like filamentous proteins like microfilaments or actin, intermediate filaments and microtubules to elicit a response in the form of mechanical movement as well as biochemical changes. The ‘springiness’ of these proteins is highlighted in their extension–contraction behaviour which is manifested as an effect of differential traction force. Atomic force microscope (AFM) provides the magic eye to visualize and quantify such force-extension/indentation events in these filamentous proteins as well as in whole cells. In this review, we have presented a summary of the current understanding and advancement of such measurements by AFM based single-molecule force spectroscopy in the context of cytoskeletal and nucleoskeletal proteins which act in tandem to facilitate mechanotransduction.

  • Synergistic roles of synaptotagmin-1 and complexin in calcium-regulated neuronal exocytosis
    Sathish Ramakrishnan, Manindra Bera, Jeff Coleman, James E Rothman, and Shyam S Krishnakumar

    eLife, eISSN: 2050084X, Pages: 1-18, Published: May 2020 eLife Sciences Publications, Ltd
    Calcium (Ca2+)-evoked release of neurotransmitters from synaptic vesicles requires mechanisms both to prevent un-initiated fusion of vesicles (clamping) and to trigger fusion following Ca2+-influx. The principal components involved in these processes are the vesicular fusion machinery (SNARE proteins) and the regulatory proteins, Synaptotagmin-1 and Complexin. Here, we use a reconstituted single-vesicle fusion assay under physiologically-relevant conditions to delineate a novel mechanism by which Synaptotagmin-1 and Complexin act synergistically to establish Ca2+-regulated fusion. We find that under each vesicle, Synaptotagmin-1 oligomers bind and clamp a limited number of ‘central’ SNARE complexes via the primary interface and introduce a kinetic delay in vesicle fusion mediated by the excess of free SNAREpins. This in turn enables Complexin to arrest the remaining free ‘peripheral’ SNAREpins to produce a stably clamped vesicle. Activation of the central SNAREpins associated with Synaptotagmin-1 by Ca2+ is sufficient to trigger rapid (<100 msec) and synchronous fusion of the docked vesicles.

  • RETREG1/FAM134B mediated autophagosomal degradation of AMFR/GP78 and OPA1 —a dual organellar turnover mechanism
    Debdatto Mookherjee, Subhrangshu Das, Rukmini Mukherjee, Manindra Bera, Swadhin Chandra Jana, Saikat Chakrabarti, and Oishee Chakrabarti

    Autophagy, ISSN: 15548627, eISSN: 15548635, Pages: 1-24, Published: 2020 Informa UK Limited
    Turnover of cellular organelles, including endoplasmic reticulum (ER) and mitochondria, is orchestrated by an efficient cellular surveillance system. We have identified a mechanism for dual regulation of ER and mitochondria under stress. It is known that AMFR, an ER E3 ligase and ER-associated degradation (ERAD) regulator, degrades outer mitochondrial membrane (OMM) proteins, MFNs (mitofusins), via the proteasome and triggers mitophagy. We show that destabilized mitochondria are almost devoid of the OMM and generate "mitoplasts". This brings the inner mitochondrial membrane (IMM) in the proximity of the ER. When AMFR levels are high and the mitochondria are stressed, the reticulophagy regulatory protein RETREG1 participates in the formation of the mitophagophore by interacting with OPA1. Interestingly, OPA1 and other IMM proteins exhibit similar RETREG1-dependent autophagosomal degradation as AMFR, unlike most of the OMM proteins. The "mitoplasts" generated are degraded by reticulo-mito-phagy - simultaneously affecting dual organelle turnover.

  • Nuclear filaments: role in chromosomal positioning and gene expression
    Manindra Bera and Kaushik Sengupta

    Nucleus, ISSN: 19491034, eISSN: 19491042, Pages: 99-110, Published: 1 January 2020 Informa UK Limited
    ABSTRACT Nuclear lamins form an elastic meshwork underlying the inner nuclear membrane and provide mechanical rigidity to the nucleus and maintain shape. Lamins also maintain chromosome positioning and play important roles in several nuclear processes like replication, DNA damage repair, transcription, and epigenetic modifications. LMNA mutations affect cardiac tissue, muscle tissues, adipose tissues to precipitate several diseases collectively termed as laminopathies. However, the rationale behind LMNA mutations and laminopathies continues to elude scientists. During interphase, several chromosomes form inter/intrachromosomal contacts inside nucleoplasm and several chromosomal loops also stretch out to make a ‘loop-cluster’ which are key players to regulate gene expressions. In this perspective, we have proposed that the lamin network in tandem with nuclear actin and myosin provide mechanical rigidity to the chromosomal contacts and facilitate loop-clusters movements. LMNA mutations thus might perturb the landscape of chromosomal contacts or loop-clusters positioning which can impair gene expression profile.

  • Chromosome territorial organization drives efficient protein complex formation: A hypothesis
    Yale Journal of Biology and Medicine, ISSN: 00440086, Pages: 541-548, Published: 2019

  • Synaptotagmin oligomers are necessary and can be sufficient to form a Ca <sup>2+</sup> -sensitive fusion clamp
    Sathish Ramakrishnan, Manindra Bera, Jeff Coleman, Shyam S. Krishnakumar, Frederic Pincet, and James E. Rothman

    FEBS Letters, ISSN: 00145793, eISSN: 18733468, Volume: 593, Pages: 154-162, Published: January 2019 Wiley
    The buttressed‐ring hypothesis, supported by recent cryo‐electron tomography analysis of docked synaptic‐like vesicles in neuroendocrine cells, postulates that prefusion SNAREpins are stabilized and organized by Synaptotagmin (Syt) ring‐like oligomers. Here, we use a reconstituted single‐vesicle fusion analysis to test the prediction that destabilizing the Syt1 oligomers destabilizes the clamp and results in spontaneous fusion in the absence of Ca2+. Vesicles in which Syt oligomerization is compromised by a ring‐destabilizing mutation dock and diffuse freely on the bilayer until they fuse spontaneously, similar to vesicles containing only v‐SNAREs. In contrast, vesicles containing wild‐type Syt are immobile as soon as they attach to the bilayer and remain frozen in place, up to at least 1 h until fusion is triggered by Ca2+.

  • Significance of 1B and 2B domains in modulating elastic properties of lamin A
    Manindra Bera, Sri Rama Koti Ainavarapu, and Kaushik Sengupta

    Scientific Reports, eISSN: 20452322, Published: 15 June 2016 Springer Science and Business Media LLC
    Nuclear lamins are type V intermediate filament proteins which form an elastic meshwork underlying the inner nuclear membrane. Lamins directly contribute to maintain the nuclear shape and elasticity. More than 400 mutations have been reported in lamin A that are involved in diseases known as laminopathies. These mutations are scattered mainly in the lamin rod domain along with some in its C-terminal domain. The contribution of the rod domain towards the elasticity of lamin A molecule was hitherto unknown. Here, we have elucidated the significance of the 1B and 2B domains of the rod in modulating the elastic behavior of lamin A by single-molecule force spectroscopy. In addition, we have also studied the network forming capacity of these domains and their corresponding viscoelastic behavior. We have shown that the 1B domain has the ability to form a lamin-like network and resists larger deformation. However at the single-molecular level, both the domains have comparable mechanical properties. The self-assembly of the 1B domain contributes to the elasticity of the lamin A network.

  • Characterization of unfolding mechanism of human lamin A Ig fold by single-molecule force spectroscopy-implications in EDMD
    Manindra Bera, Hema Chandra Kotamarthi, Subarna Dutta, Angana Ray, Saptaparni Ghosh, Dhananjay Bhattacharyya, Sri Rama Koti Ainavarapu, and Kaushik Sengupta

    Biochemistry, ISSN: 00062960, eISSN: 15204995, Pages: 7247-7258, Published: 25 November 2014 American Chemical Society (ACS)
    A- and B-type lamins are intermediate filament proteins constituting the nuclear lamina underneath the nuclear envelope thereby conferring proper shape and mechanical rigidity to the nucleus. Lamin proteins are also shown to be related diversely to basic nuclear processes. More than 400 mutations in human lamin A protein alone have been reported to produce at least 11 different disease conditions jointly termed as laminopathies. These mutations in lamin A are scattered throughout its helical rod domain, as well as the C-terminal domain containing the conserved Ig-fold region. The commonality of phenotypes in all these diseases is characterized by misshapen nuclei of the affected tissues which might stem from altered rigidity of the supporting lamina hence lamins. Here we have focused on autosomal dominant Emery-Dreifuss Muscular Dystrophy, one such laminopathy where R453W is the causative mutation located in the Ig domain of lamin A. We have investigated by single-molecule force spectroscopy how a stretching mechanical perturbation senses the destabilizing effect of the mutation in the lamin A Ig domain and compared the mechanoelastic properties of the mutant R453W with that of the wild-type in conjunction with steered molecular dynamics. Furthermore, we have shown the interaction of Ig domain with emerin, another key player and interacting partner in the pathogenesis of EDMD, is disrupted in the R453W mutant. This altered mechanoresistance of Ig domain itself and consequent uncoupling of lamin A-emerin interaction might underlie the altered mechanotransduction properties of EDMD affected nuclei.

RECENT SCHOLAR PUBLICATIONS

  • Molecular determinants of complexin clamping and activation function
    M Bera, S Ramakrishnan, J Coleman, SS Krishnakumar, JE Rothman
    Elife 11 2022

  • RETREG1/FAM134B mediated autophagosomal degradation of AMFR/GP78 and OPA1—a dual organellar turnover mechanism
    D Mookherjee, S Das, R Mukherjee, M Bera, SC Jana, S Chakrabarti, ...
    Autophagy 17 (7), 1729-1752 2021

  • Pulling the springs of a cell by single-molecule force spectroscopy
    C Mukherjee, M Bera, SR Koti Ainavarapu, K Sengupta
    Emerging Topics in Life Sciences 5 (1), 77-87 2021

  • Molecular determinants of complexin clamping in reconstituted single-vesicle fusion
    M Bera, S Ramakrishnan, J Coleman, SS Krishnakumar, JE Rothman
    bioRxiv 2021

  • Synergistic roles of Synaptotagmin-1 and complexin in calcium-regulated neuronal exocytosis
    S Ramakrishnan, M Bera, J Coleman, JE Rothman, SS Krishnakumar
    Elife 9, e54506 2020

  • Dissecting the Synergistic Roles of Synaptotagmin and Complexin in Ca2+-Regulated Exocytosis
    S Ramakrishnan, M Bera, J Coleman, F Pincet, J Rothman, ...
    Biophysical Journal 118 (3), 488a 2020

  • Nuclear filaments: role in chromosomal positioning and gene expression
    M Bera, K Sengupta
    Nucleus 11 (1), 99-110 2020

  • Focus: Organelles: Chromosome Territorial Organization Drives Efficient Protein Complex Formation: A Hypothesis
    M Bera, RVK Sundaram
    The Yale Journal of Biology and Medicine 92 (3), 541 2019

  • Independent Yet Synergistic Roles of Synaptotagmin-1 and Complexin in Calcium Regulated Neuronal Exocytosis
    S Ramakrishnan, M Bera, J Coleman, JE Rothman, SS Krishnakumar
    bioRxiv 2019

  • Nuclear deformation and anchorage defect induced by DCM mutants in lamin A
    M Bera, R Kumar, B Sinha, K Sengupta
    bioRxiv, 611665 2019

  • Synaptotagmin oligomers are necessary and can be sufficient to form a Ca2+‐sensitive fusion clamp
    S Ramakrishnan, M Bera, J Coleman, SS Krishnakumar, F Pincet, ...
    FEBS letters 593 (2), 154-162 2019

  • Gnter Blobel: Pioneer of molecular cell biology (1936–2018)
    Blobel Laboratory Trainees
    Journal of Cell Biology 217 (4), 1163-1167 2018

  • Significance of 1B and 2B domains in modulating elastic properties of lamin A
    M Bera, SRK Ainavarapu, K Sengupta
    Scientific reports 6 (1), 1-12 2016

  • Characterization of Unfolding Mechanism of Human Lamin A Ig Fold by Single-Molecule Force Spectroscopy Implications in EDMD
    M Bera, HC Kotamarthi, S Dutta, A Ray, S Ghosh, D Bhattacharyya, ...
    Biochemistry 53 (46), 7247-7258 2014

MOST CITED SCHOLAR PUBLICATIONS

  • Synaptotagmin oligomers are necessary and can be sufficient to form a Ca2+‐sensitive fusion clamp
    S Ramakrishnan, M Bera, J Coleman, SS Krishnakumar, F Pincet, ...
    FEBS letters 593 (2), 154-162 2019
    Citations: 29

  • Characterization of Unfolding Mechanism of Human Lamin A Ig Fold by Single-Molecule Force Spectroscopy Implications in EDMD
    M Bera, HC Kotamarthi, S Dutta, A Ray, S Ghosh, D Bhattacharyya, ...
    Biochemistry 53 (46), 7247-7258 2014
    Citations: 27

  • Synergistic roles of Synaptotagmin-1 and complexin in calcium-regulated neuronal exocytosis
    S Ramakrishnan, M Bera, J Coleman, JE Rothman, SS Krishnakumar
    Elife 9, e54506 2020
    Citations: 17

  • Significance of 1B and 2B domains in modulating elastic properties of lamin A
    M Bera, SRK Ainavarapu, K Sengupta
    Scientific reports 6 (1), 1-12 2016
    Citations: 16

  • RETREG1/FAM134B mediated autophagosomal degradation of AMFR/GP78 and OPA1—a dual organellar turnover mechanism
    D Mookherjee, S Das, R Mukherjee, M Bera, SC Jana, S Chakrabarti, ...
    Autophagy 17 (7), 1729-1752 2021
    Citations: 13

  • Nuclear filaments: role in chromosomal positioning and gene expression
    M Bera, K Sengupta
    Nucleus 11 (1), 99-110 2020
    Citations: 9

  • Molecular determinants of complexin clamping and activation function
    M Bera, S Ramakrishnan, J Coleman, SS Krishnakumar, JE Rothman
    Elife 11 2022
    Citations: 2

  • Molecular determinants of complexin clamping in reconstituted single-vesicle fusion
    M Bera, S Ramakrishnan, J Coleman, SS Krishnakumar, JE Rothman
    bioRxiv 2021
    Citations: 1

  • Focus: Organelles: Chromosome Territorial Organization Drives Efficient Protein Complex Formation: A Hypothesis
    M Bera, RVK Sundaram
    The Yale Journal of Biology and Medicine 92 (3), 541 2019
    Citations: 1