Andrea Musacchio

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Andrea Musacchio
AndreaMusacchio.png
Born
Andrea Musacchio

(1964-07-11) July 11, 1964 (age 59)
Rome, Italy
Nationality Italian
Alma mater University of Rome Tor Vergata, European Molecular Biology Laboratory
Scientific career
Fields Crystallography
Institutions Harvard Medical School, European Institute of Oncology, Max Planck Institute for Molecular Physiology
Doctoral advisor Matti Saraste
Other academic advisorsGianni Cesareni

Andrea Musacchio (born July 11, 1964) [1] is an Italian structural biologist. He is Max Planck director at the Institute of Molecular Physiology in Dortmund. He is also Honorary Professor at the Center for Medical Biotechnology at the University of Duisburg-Essen. He was named European Molecular Biology Organization member in 2009. [2]

Contents

Education and career

Musacchio received a Laurea in Biology from the University of Rome Tor Vergata summa cum laude in 1990, and earned his Ph.D., summacum laude, from the Heidelberg University in 1995 working at the European Molecular Biology Laboratory. For his postdoctoral studies he joined Stephen C. Harrison laboratory at the Harvard Medical School in Boston. In 1999 he returned to Italy to found his laboratory at the European Institute of Oncology in Milan, where he started working on mechanisms of cell division. He was a European Molecular Biology Organization Young Investigator from 2000-2004. Musacchio moved to Dortmund in 2011 to direct the Department of Mechanistic Cell Biology at the Max Planck Institute for Molecular Physiology [3]

Research

Musacchio approached structural biology during his Ph.D., contributing to the determination of the first crystallographic structures of the SH3 [4] and PH [5] domains. During his post-doctoral training, he was involved in the determination of the clathrin triskelion structure, [6] one of the first studies combining X-ray crystallography and electron microscopy. As an independent scientist, his interests focused on the understanding of the molecular basis of mitosis, with emphasis on the spindle assembly checkpoint. Since the early days, Musacchio's lab adopted a multi-disciplinary approach merging structural biology, biochemistry and cellular biology, this way gaining comprehensive views on protein functions in living cells. [7] He is best known for his work on Mad1/Mad2 complexes, [8] [9] which led to the formulation of the template model, [10] and for his contributions to the understanding of the role of the kinase Aurora B, Mps1 and Haspin in mitosis. [11] [12] [13] [14] In 2008, the structure of the Ndc80 complex [15] set the foundation of a new line of his investigations on kinetochore assembly and attachment to microtubules [16] [17] [18]

Personal life

Musacchio spent his childhood in Rome, where he grew to be a strong supporter of A.S. Roma. He has started embracing Borussia Dortmund.

He is married and father of two boys.

Related Research Articles

<span class="mw-page-title-main">Spindle apparatus</span> Feature of biological cell structure

In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a process that produces genetically identical daughter cells, or the meiotic spindle during meiosis, a process that produces gametes with half the number of chromosomes of the parent cell.

<span class="mw-page-title-main">Anaphase-promoting complex</span> Cell-cycle regulatory complex

Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during metaphase of mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

<span class="mw-page-title-main">Kinetochore</span> Protein complex that allows microtubules to attach to chromosomes during cell division

A kinetochore is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as a freshman in 1932.

Mad2 is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition. The Mad2 gene was first identified in the yeast S. cerevisiae in a screen for genes which when mutated would confer sensitivity to microtubule poisons. The human orthologues of Mad2 were first cloned in a search for human cDNAs that would rescue the microtubule poison-sensitivity of a yeast strain in which a kinetochore binding protein was missing. The protein was shown to be present at unattached kinetochores and antibody inhibition studies demonstrated it was essential to execute a block in the metaphase-to-anaphase transition in response to the microtubule poison nocodazole. Subsequent cloning of the Xenopus laevis orthologue, facilitated by the sharing of the human sequence, allowed for the characterization of the mitotic checkpoint in egg extracts.

<span class="mw-page-title-main">MAD1L1</span> Protein-coding gene in the species Homo sapiens

Mitotic spindle assembly checkpoint protein MAD1 is a protein that in humans is encoded by the MAD1L1 gene.

<span class="mw-page-title-main">Aurora kinase B</span> Protein

Aurora kinase B is a protein that functions in the attachment of the mitotic spindle to the centromere.

<span class="mw-page-title-main">CDC20</span> Protein-coding gene in the species Homo sapiens

The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase. The APC/CCdc20 protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows the cell to exit from mitosis. A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle.

<span class="mw-page-title-main">BUB1</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 is an enzyme that in humans is encoded by the BUB1 gene.

<span class="mw-page-title-main">BUB1B</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint serine/threonine-protein kinase BUB1 beta is an enzyme that in humans is encoded by the BUB1B gene. Also known as BubR1, this protein is recognized for its mitotic roles in the spindle assembly checkpoint (SAC) and kinetochore-microtubule interactions that facilitate chromosome migration and alignment. BubR1 promotes mitotic fidelity and protects against aneuploidy by ensuring proper chromosome segregation between daughter cells. BubR1 is proposed to prevent tumorigenesis.

<span class="mw-page-title-main">Dynactin</span>

Dynactin is a 23 subunit protein complex that acts as a co-factor for the microtubule motor cytoplasmic dynein-1. It is built around a short filament of actin related protein-1 (Arp1).

<span class="mw-page-title-main">MAD2L1</span> Protein-coding gene in the species Homo sapiens

Mitotic spindle assembly checkpoint protein MAD2A is a protein that in humans is encoded by the MAD2L1 gene.

<span class="mw-page-title-main">CDC27</span> Protein-coding gene in the species Homo sapiens

Cell division cycle protein 27 homolog is a protein that in humans is encoded by the CDC27 gene.

<span class="mw-page-title-main">NDC80</span> Protein-coding gene in the species Homo sapiens

Kinetochore protein NDC80 homolog is a protein that in humans is encoded by the NDC80 gene.

<span class="mw-page-title-main">BUB3</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint protein BUB3 is a protein that in humans is encoded by the BUB3 gene.

<span class="mw-page-title-main">NUF2</span> Protein-coding gene in the species Homo sapiens

Kinetochore protein Nuf2 is a protein that in humans is encoded by the NUF2 gene.

<span class="mw-page-title-main">TRIP13</span> Protein-coding gene in the species Homo sapiens

TRIP13 is a mammalian gene that encodes the thyroid receptor-interacting protein 13. In budding yeast, the analog for TRIP13 is PCH2. TRIP13 is a member of the AAA+ ATPase family, a family known for mechanical forces derived from ATP hydrolase reactions. The TRIP13 gene has been shown to interact with a variety of proteins and implicated in a few diseases, notably interacting with the ligand binding domain of thyroid hormone receptors, and may play a role in early-stage non-small cell lung cancer. However, recent evidence implicates TRIP13 in various cell cycle phases, including meiosis G2/Prophase and during the Spindle Assembly checkpoint (SAC). Evidence shows regulation to occur through the HORMA domains, including Hop1, Rev7, and Mad2. Of note, Mad2's involvement in the SAC is shown to be affected by TRIP13 Due to TRIP13's role in cell cycle arrest and progression, it may present opportunity as a therapeutic candidate for cancers.

<span class="mw-page-title-main">ZW10</span>

Centromere/kinetochore protein zw10 homolog is a protein that in humans is encoded by the ZW10 gene. This gene encodes a protein that is one of many involved in mechanisms to ensure proper chromosome segregation during cell division. The encoded protein binds to centromeres during the prophase, metaphase, and early anaphase cell division stages and to kinetochore microtubules during metaphase.

<span class="mw-page-title-main">SPC24</span> Protein-coding gene in the species Homo sapiens

Kinetochore protein Spc24 is a protein that in humans is encoded by the SPC24 gene.

<span class="mw-page-title-main">Mad1</span>

Mad1 is a non-essential protein which in yeast has a function in the spindle assembly checkpoint (SAC). This checkpoint monitors chromosome attachment to spindle microtubules and prevents cells from starting anaphase until the spindle is built up. The name Mad refers to the observation that mutant cells are mitotic arrest deficient (MAD) during microtubule depolymerization. Mad1 recruits the anaphase inhibitor Mad2 to unattached kinetochores and is essential for Mad2-Cdc20 complex formation in vivo but not in vitro. In vivo, Mad1 acts as a competitive inhibitor of the Mad2-Cdc20 complex. Mad1 is phosphorylated by Mps1 which then leads together with other activities to the formation of the mitotic checkpoint complex (MCC). Thereby it inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C). Homologues of Mad1 are conserved in eukaryotes from yeast to mammals.

References

  1. ↑ "Musacchio, Andrea". www.mpg.de. Retrieved 2024-01-12.
  2. ↑ 2009 EMBO Press Release Archived 2014-12-09 at the Wayback Machine
  3. ↑ Musacchio A. (2012). "Andrea Musacchio". Current Biology. 22 (14): R552–R554. doi: 10.1016/j.cub.2012.06.024 . PMID   23012739.
  4. ↑ Musacchio, A; Noble, M; Pauptit, R; Wierenga, R; Saraste, M (Oct 29, 1992). "Crystal structure of a Src-homology 3 (SH3) domain". Nature. 359 (6398): 851–5. Bibcode:1992Natur.359..851M. doi:10.1038/359851a0. PMID   1279434. S2CID   4254768.
  5. ↑ Macias, MJ; Musacchio, A; Ponstingl, H; Nilges, M; Saraste, M; Oschkinat, H (Jun 23, 1994). "Structure of the pleckstrin homology domain from beta-spectrin". Nature. 369 (6482): 675–7. Bibcode:1994Natur.369..675M. doi:10.1038/369675a0. PMID   8208297. S2CID   4358947.
  6. ↑ Musacchio, A; Smith, CJ; Roseman, AM; Harrison, SC; Kirchhausen, T; Pearse, BM (Jun 1999). "Functional Organization of Clathrin in Coats: Combining Electron Cryomicroscopy and X-Ray Crystallography". Molecular Cell. 3 (6): 761–70. doi: 10.1016/S1097-2765(01)80008-3 . PMID   10394364.
  7. ↑ Nasmyth, K (Mar 25, 2005). "How do so few control so many?". Cell. 120 (6): 739–46. doi: 10.1016/j.cell.2005.03.006 . PMID   15797376. S2CID   18831437.
  8. ↑ Sironi, L; Mapelli, M; Knapp, S; De Antoni, A; Jeang, KT; Musacchio, A (May 15, 2002). "Crystal structure of the tetrameric Mad1-Mad2 core complex: implications of a 'safety belt' binding mechanism for the spindle checkpoint". The EMBO Journal. 21 (10): 2496–506. doi:10.1093/emboj/21.10.2496. PMC   126000 . PMID   12006501.
  9. ↑ Mapelli, M; Massimiliano, L; Santaguida, S; Musacchio, A (Nov 16, 2007). "The Mad2 conformational dimer: structure and implications for the spindle assembly checkpoint" (PDF). Cell. 131 (4): 730–43. doi:10.1016/j.cell.2007.08.049. hdl: 2434/65744 . PMID   18022367. S2CID   17345925.
  10. ↑ De Antoni, A; Pearson, CG; Cimini, D; Canman, JC; Sala, V; Nezi, L; Mapelli, M; Sironi, L; Faretta, M; Salmon, ED; Musacchio, A (Feb 8, 2005). "The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint". Current Biology. 15 (3): 214–25. doi: 10.1016/j.cub.2005.01.038 . PMID   15694304. S2CID   3224122.
  11. ↑ De Antoni, A; Maffini, S; Knapp, S; Musacchio, A; Santaguida, S (Oct 15, 2012). "A small-molecule inhibitor of Haspin alters the kinetochore functions of Aurora B." (PDF). The Journal of Cell Biology. 199 (2): 269–84. doi:10.1083/jcb.201205119. PMC   3471222 . PMID   23071153.
  12. ↑ Santaguida, S; Vernieri, C; Villa, F; Ciliberto, A; Musacchio, A (Apr 20, 2011). "Evidence that Aurora B is implicated in spindle checkpoint signalling independently of error correction". The EMBO Journal. 30 (8): 1508–19. doi:10.1038/emboj.2011.70. PMC   3102279 . PMID   21407176.
  13. ↑ Santaguida, S; Tighe, A; D'Alise, AM; Taylor, SS; Musacchio, A (Jul 12, 2010). "Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine". The Journal of Cell Biology. 190 (1): 73–87. doi:10.1083/jcb.201001036. PMC   2911657 . PMID   20624901.
  14. ↑ Sessa, F; Mapelli, M; Ciferri, C; Tarricone, C; Areces, LB; Schneider, TR; Stukenberg, PT; Musacchio, A (Apr 29, 2005). "Mechanism of Aurora B activation by INCENP and inhibition by hesperadin". Molecular Cell. 18 (3): 379–91. doi: 10.1016/j.molcel.2005.03.031 . PMID   15866179.
  15. ↑ Ciferri, C; Pasqualato, S; Screpanti, E; Varetti, G; Santaguida, S; Dos Reis, G; Maiolica, A; Polka, J; De Luca, JG; De Wulf, P; Salek, M; Rappsilber, J; Moores, CA; Salmon, ED; Musacchio, A (May 2, 2008). "Implications for kinetochore-microtubule attachment from the structure of an engineered Ndc80 complex". Cell. 133 (3): 427–39. doi:10.1016/j.cell.2008.03.020. PMC   4754795 . PMID   18455984.
  16. ↑ Santaguida, S; Musacchio, A (Sep 2, 2009). "The life and miracles of kinetochores". The EMBO Journal. 28 (17): 2511–31. doi:10.1038/emboj.2009.173. PMC   2722247 . PMID   19629042.
  17. ↑ Petrovic, A; Mosalaganti, S; Keller, J; Mattiuzzo, M; Overlack, K; Krenn, V; De Antoni, A; Wohlgemuth, S; Cecatiello, V; Pasqualato, S; Raunser, S; Musacchio, A (Feb 20, 2014). "Modular assembly of RWD domains on the Mis12 complex underlies outer kinetochore organization". Molecular Cell. 53 (4): 591–605. doi: 10.1016/j.molcel.2014.01.019 . hdl: 10281/397721 . PMID   24530301.
  18. ↑ Basilico, F; Maffini, S; Weir, JR; Prumbaum, D; Rojas, AM; Zimniak, T; De Antoni, A; Jeganethan, S; Voss, B; van Gerwen, S; Krenn, V; Massimiliano, L; Valencia, A; Vetter, IR; Herzog, F; Raunser, S; Pasqualato, S; Musacchio, A (Jul 8, 2014). "The pseudo GTPase CENP-M drives human kinetochore assembly". eLife. 3: e02978. doi: 10.7554/elife.02978 . PMC   4080450 . PMID   25006165.
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