David D. Sabatini

Last updated
David Domingo Sabatini
Alma mater
Awards E.B. Wilson Medal (1986)
Scientific career
Fields Cell biology
Institutions Rockefeller University, New York University
Thesis  (1966)
Notable studentsEnrique Rodriguez-Boulan [1]

David Domingo Sabatini is an Argentine-American cell biologist and the Frederick L. Ehrman Professor Emeritus of Cell Biology in the Department of Cell Biology at New York University School of Medicine, [2] which he chaired from 1972 to 2011. Sabatini's major research interests have been on the mechanisms responsible for the structural complexity of the eukaryotic cell. Throughout his career, Sabatini has been recognized for his efforts in promoting science in Latin America. [3]

Contents

Early life and education

Sabatini is a native of Argentina, and attended medical school in Rosario at the National University of the Litoral. He began his research career at the University of Buenos Aires, in the laboratory of Eduardo De Robertis, a founder of modern cell biology, where he developed skills in electron microscopy. In 1961, as a Rockefeller Foundation fellow, he traveled to the United States, first for a six-month stint at Yale University to work with histochemist Russell Barnett, and then to work with George Palade and Philip Siekevitz at the Rockefeller University. Whilst at Yale he introduced glutaraldehyde as a fixative for electron microscopy and cytochemistry. [4] After a year as a postdoctoral fellow at Rockefeller, Sabatini entered the Rockefeller graduate program from which he received a PhD in 1966 for studies on protein translation by ribosomes attached to endoplasmic reticulum membranes. [5] [6]

Research overview

Sabatini's research has focused on the mechanisms by which proteins are targeted to different organelles within the cell. His early work studied co-translational targeting of ribosomes to the endoplasmic reticulum and helped establish the hypothesis that signal peptides direct protein traffic to cellular compartments. [7] He later focused on trafficking from the Golgi apparatus to secretory vesicles and to the plasma membrane and in particular the mechanisms that address membrane proteins to the different surface domains of epithelial cells for which he employed viral infected epithelial monolayers. [8]

Academic career

After finishing his PhD, Sabatini joined the faculty at Rockefeller and in his own laboratory continued studies on protein trafficking in the ER. With a group of young associates (Nica Borgese, Mark Adelman, and Gert Kreibich), collaborating with Gunter Blobel, he continued research on the mechanism that ensures the co-translational translocation and vectorial discharge of nascent polypeptides into and across the endoplasmic reticulum membrane. In in vitro experiments they discovered that the microsomal membrane protected the N-terminal portion of nascent polypeptides synthesized in membrane bound ribosomes from proteolytic attack by exogenous enzymes. [9] [10] [11] [12] These studies strongly implicated the N-terminal portions of nascent polypeptides in establishing and maintaining the association of bound ribosomes with ER membranes.

Largely based on these findings, in 1971 Blobel and Sabatini proposed a speculative model [13] that later came to be known as the "signal hypothesis". For a discussion of the genesis and evolution of the signal hypothesis see LaBonte, 2017 [14] In the 1971 paper, Blobel and Sabatini proposed that “all mRNAs to be translated on bound ribosomes have a common feature, such as several codons near their 5’ end, not present in mRNAs which are to be translated on free ribosomes” and that “the resulting common sequence of amino acids near the N-termini of the nascent chains, or a modification of it, would then be recognized by a factor mediating the binding to the membrane." They proposed that "This binding factor could be a soluble protein, which recognizes both a site on the large ribosomal subunit and a site on the membrane.” [15] A decade later, Walter and Blobel demonstrated the existence of a Signal Recognition Protein (SRP) that mediates the binding of the ribosome and the signal sequence within the nascent chain to the membrane. [16] [17] In 1982, a cognate receptor for the Signal Recognition Particle (SRP) was discovered and characterized in the ER membrane. [18] [19] [20]

In 1972, Sabatini moved his laboratory to the New York University School of Medicine to become the chair of the Department of Cell Biology, [21] where he assembled a group that focused on the study of membrane and organelle biogenesis. [22] Initially, that work placed a primary emphasis on identifying structural features of secretory, lysosomal [23] and integral membrane proteins [24] that are synthesized on membrane bound ribosomes, address them to specific subcellular locations and determine their disposition within a membrane.

In the late 1970s, in collaboration with Marcelino Cereijido [25] he introduced the now widely used MDCK cell culture system for the study of epithelial cell polarity and together with Enrique Rodriguez-Boulan reported the landmark discovery of the asymmetric budding of specific enveloped viruses from the different surfaces of epithelial cells. [26] [27]

Honors and awards

Sabatini was elected a fellow of the American Academy of Arts and Sciences in 1980 [28] and became a member of the U.S. National Academy of Sciences in 1985. [29] In 1986, together with Günter Blobel, he received the E.B. Wilson Medal, the highest honor of the American Society of Cell Biology, of which he was president in 1978-79. [30] He was selected to give the ASCB's Keith R. Porter Lecture in 1983. [31] [32]

He is a member of the U.S. National Academy of Medicine, a member of the American Philosophical Society, [33] and a foreign associate of the French Academy of Sciences. He was awarded the Charles Leopold Mayer Prize (1986) and the Grande Médaille (2003) by the French Academy of Sciences, and in 2006 he was named a Chevalier de la Légion d’honneur.

Personal life

Sabatini's wife Zulema is also from Argentina and is a medical doctor specializing in pathology. The couple's two sons are both current or former MD–PhD academic research scientists and Howard Hughes Medical Institute investigators: Bernardo L. Sabatini is a neuroscientist at Harvard Medical School and David M. Sabatini was a cell biologist at the Massachusetts Institute of Technology until he resigned in 2022. [34] [35] [36]

Related Research Articles

<span class="mw-page-title-main">Endoplasmic reticulum</span> Cell organelle that synthesizes, folds and processes proteins

The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.

<span class="mw-page-title-main">Endomembrane system</span> Membranes in the cytoplasm of a eukaryotic cell

The endomembrane system is composed of the different membranes (endomembranes) that are suspended in the cytoplasm within a eukaryotic cell. These membranes divide the cell into functional and structural compartments, or organelles. In eukaryotes the organelles of the endomembrane system include: the nuclear membrane, the endoplasmic reticulum, the Golgi apparatus, lysosomes, vesicles, endosomes, and plasma (cell) membrane among others. The system is defined more accurately as the set of membranes that forms a single functional and developmental unit, either being connected directly, or exchanging material through vesicle transport. Importantly, the endomembrane system does not include the membranes of plastids or mitochondria, but might have evolved partially from the actions of the latter.

Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.

A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in TMDs are often hydrophobic, although proteins such as membrane pumps and ion channels can contain polar residues. TMDs vary greatly in size and hydrophobicity; they may adopt organelle-specific properties.

The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes.

A signal peptide is a short peptide present at the N-terminus of most newly synthesized proteins that are destined toward the secretory pathway. These proteins include those that reside either inside certain organelles, secreted from the cell, or inserted into most cellular membranes. Although most type I membrane-bound proteins have signal peptides, most type II and multi-spanning membrane-bound proteins are targeted to the secretory pathway by their first transmembrane domain, which biochemically resembles a signal sequence except that it is not cleaved. They are a kind of target peptide.

The translocon is a complex of proteins associated with the translocation of polypeptides across membranes. In eukaryotes the term translocon most commonly refers to the complex that transports nascent polypeptides with a targeting signal sequence into the interior space of the endoplasmic reticulum (ER) from the cytosol. This translocation process requires the protein to cross a hydrophobic lipid bilayer. The same complex is also used to integrate nascent proteins into the membrane itself. In prokaryotes, a similar protein complex transports polypeptides across the (inner) plasma membrane or integrates membrane proteins. In either case, the protein complex are formed from Sec proteins, with the heterotrimeric Sec61 being the channel. In prokaryotes, the homologous channel complex is known as SecYEG.

The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amine group is bonded to the carboxylic group of another amino acid, making it a chain. That leaves a free carboxylic group at one end of the peptide, called the C-terminus, and a free amine group on the other end called the N-terminus. By convention, peptide sequences are written N-terminus to C-terminus, left to right (in LTR writing systems). This correlates the translation direction to the text direction, because when a protein is translated from messenger RNA, it is created from the N-terminus to the C-terminus, as amino acids are added to the carboxyl end of the protein.

In cell biology, microsomes are heterogeneous vesicle-like artifacts re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, living cells.

Sec61, termed SecYEG in prokaryotes, is a membrane protein complex found in all domains of life. As the core component of the translocon, it transports proteins to the endoplasmic reticulum in eukaryotes and out of the cell in prokaryotes. It is a doughnut-shaped pore through the membrane with 3 different subunits (heterotrimeric), SecY (α), SecE (γ), and SecG (β). It has a region called the plug that blocks transport into or out of the ER. This plug is displaced when the hydrophobic region of a nascent polypeptide interacts with another region of Sec61 called the seam, allowing translocation of the polypeptide into the ER lumen.

<span class="mw-page-title-main">Oligosaccharyltransferase</span> Class of enzymes

Oligosaccharyltransferase or OST (EC 2.4.1.119) is a membrane protein complex that transfers a 14-sugar oligosaccharide from dolichol to nascent protein. It is a type of glycosyltransferase. The sugar Glc3Man9GlcNAc2 (where Glc=Glucose, Man=Mannose, and GlcNAc=N-acetylglucosamine) is attached to an asparagine (Asn) residue in the sequence Asn-X-Ser or Asn-X-Thr where X is any amino acid except proline. This sequence is called a glycosylation sequon. The reaction catalyzed by OST is the central step in the N-linked glycosylation pathway.

A secretory protein is any protein, whether it be endocrine or exocrine, which is secreted by a cell. Secretory proteins include many hormones, enzymes, toxins, and antimicrobial peptides. Secretory proteins are synthesized in the endoplasmic reticulum.

<span class="mw-page-title-main">Signal recognition particle receptor</span>

Signal recognition particle (SRP) receptor, also called the docking protein, is a dimer composed of 2 different subunits that are associated exclusively with the rough ER in mammalian cells. Its main function is to identify the SRP units. SRP is a molecule that helps the ribosome-mRNA-polypeptide complexes to settle down on the membrane of the endoplasmic reticulum.

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

Ribophorins are dome shaped transmembrane glycoproteins which are located in the membrane of the rough endoplasmic reticulum, but are absent in the membrane of the smooth endoplasmic reticulum. There are two types of ribophorines: ribophorin I and II. These act in the protein complex oligosaccharyltransferase (OST) as two different subunits of the named complex. Ribophorin I and II are only present in eukaryote cells.

<span class="mw-page-title-main">Outline of cell biology</span> Overview of and topical guide to cell biology

The following outline is provided as an overview of and topical guide to cell biology:

<span class="mw-page-title-main">RRBP1</span> Protein-coding gene in the species Homo sapiens

Ribosome-binding protein 1, also referred to as p180, is a protein that in humans is encoded by the RRBP1 gene.

<span class="mw-page-title-main">Sec61 alpha 1</span>

Protein transport protein Sec61 subunit alpha isoform 1 is a protein encoded by the SEC61A1 gene in humans.

In cell biology, membrane bound polyribosomes are attached to a cell's endoplasmic reticulum. When certain proteins are synthesized by a ribosome they can become "membrane-bound". The newly produced polypeptide chains are inserted directly into the endoplasmic reticulum by the ribosome and are then transported to their destinations. Bound ribosomes usually produce proteins that are used within the cell membrane or are expelled from the cell via exocytosis.

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

Signal peptidases are enzymes that convert secretory and some membrane proteins to their mature or pro forms by cleaving their signal peptides from their N-termini.

A target peptide is a short peptide chain that directs the transport of a protein to a specific region in the cell, including the nucleus, mitochondria, endoplasmic reticulum (ER), chloroplast, apoplast, peroxisome and plasma membrane. Some target peptides are cleaved from the protein by signal peptidases after the proteins are transported.

References

  1. ↑ "Richard Lounsbery Foundation | Sabatini".
  2. ↑ "David D. Sabatini". New York University. Retrieved 5 April 2017.
  3. ↑ Adesnik M. 2002. David Sabatini--a lifelong fascination with organelles. TRENDS in Cell Biology. 12:347-49
  4. ↑ Sabatini DD, Bensch K, Barrnett RJ. 1963. Cytochemistry and electron microscopy. The preservation of cellular ultrastructure and enzymatic activity by aldehyde fixation. J. Cell Biol. 17:19-58
  5. ↑ Sabatini DD, Tashiro Y, Palade GE. 1966. On the attachment of ribosomes to microsomal membranes. J. Mol. Biol. 19:503-24; Redman CM, Sabatini DD. 1966. Vectorial discharge of peptides released by puromycin from attached ribosomes. Proc. Natl. Acad. Sci. USA 56:608-15
  6. ↑ Redman CM, Sabatini DD. 1966. Vectorial discharge of peptides released by puromycin from attached ribosomes. Proc. Natl. Acad. Sci. USA 56:608–15
  7. ↑ Adesnik M. 2002. David Sabatini--a lifelong fascination with organelles. TRENDS in Cell Biology. 12:347-49
  8. ↑ IN AWE OF SUBCELLULAR COMPLEXITY: 50 Years of Trespassing Boundaries Within the Cell David D. Sabatini Annual Review of Cell and Developmental Biology Vol. 21, 2005
  9. ↑ Sabatini, D.D. and Blobel (1970). Controlled proteolysis of nascent polypeptides in rat liver cell fractions. II. Location of the polypeptides in rough microsomes. J Cell Biol 45, 146-157.
  10. ↑ Blobel G. and Sabatini, D.D., (1970).Controlled proteolysis of nascent polypeptides in rat liver cell fractions.I. Location of the polypeptides within ribosomes. J Cell Biol 45, 130-145
  11. ↑ Adelman MR, Blobel G, Sabatini DD. 1973a. An improved cell fractionation procedure for the preparation of rat liver membrane-bound ribosomes. J. Cell Biol. 56:191–205
  12. ↑ Borgese N, Mok W, Kreibich G, Sabatini DD. 1974 Ribosomal-membrane interaction: in vitro binding of ribosomes to microsomal membranes. J Mol Biol. 25:559-80(
  13. ↑ G. Blobel, D.D. Sabatini,. Ribosome-membrane interaction in eukaryotic cells. 1971 Biomembranes, 2, 193–95
  14. ↑ LaBonte, ML. 2017. Blobel and Sabatini's "Beautiful Idea": Visual Representations of the Conception and Refinement of the Signal Hypothesis. J Hist Biol. 2017 50(4):797-833
  15. ↑ G. Blobel, D.D. Sabatini,. Ribosome-membrane interactions in eukaryotic cells. 1971 Biomembranes, 2, 193–95
  16. ↑ Walter P. & Blobel G., 1981, Translocation of proteins across the endoplasmic reticulum II, Signal recognition protein(SRP) mediates the selective binding to microsomal membrane of in-vitro- assembled polysomes synthesizing secretory proteins. J. Cell Biol. 91:551-56
  17. ↑ Walter P. & Blobel G., 1983, Disassembly and reconstitution of signal recognition particle. Cell 54: 525-33
  18. ↑ Gilmore R. Blobel G. Walter P 1982a. Protein Translocation across the endoplasmic reticulum I. Detection in the microsomal membrane of a receptor for the signal recognition particle. J. Cell Biol. 95:463-69.
  19. ↑ Gilmore R. Walter P. Blobel G. 1982b Protein translocation across the endoplasmic reticulum II. Isolation and Characterization of the signal recognition particle receptor. J.Cell Biol. 95:470-77
  20. ↑ Meyer DI, Krause E, Dobberstein B.,1982). Secretory protein translocation across membranes—the role of the “docking protein” Nature 297:647-50
  21. ↑ Adesnik, Milton (July 2002). "David Sabatini – a lifelong fascination with organelles". Trends in Cell Biology. 12 (7): 347–349. doi:10.1016/S0962-8924(02)02296-1. PMID   12185852.
  22. ↑ Adesnik M. 2002. David Sabatini – a lifelong fascination with organelles. TRENDS in Cell Biology. 12:347-49
  23. ↑ Rosenfeld MG, Krebich G, Popov D, Kato, K Sabatini DD 1982, Biosynthesis of lysosomal hydrolases: their synthesis in bound polysomes and the role of co- and post- translational processing in determining their subcellular substitution J. Cell Biol. 93:135-43)
  24. ↑ Monier, S, Van Luc P, Kreibich G, Sabatini DD, Adesnik M. (1988). Signals for the incorporation and orientation of Cytochrome P450 in the endoplasmic reticulum membranes. J Cell Biol. 107:457-70
  25. ↑ Cereijido M, Robbins ES, Dolan WJ, Rotunno CA, Sabatini DD. 1978. Polarized monolayers formed by epithelial cells on a permeable and transculent support. J. Cell Biol. 77:853-80
  26. ↑ Rodriguez-Boulan ER, Sabatini DD. 1978. Asymmetric budding of viruses in epithelial monolayers: a model system for study of epithelial polarity. Proc. Natl. Acad. Sci. USA 75:5071-75
  27. ↑ Coming to Grips with Cell Surface polarity. Simons K. 2017 Nat Rev Mol Cell Biol. 2017 18:278
  28. ↑ "David Sabatini". American Academy of Arts and Sciences. Retrieved 5 April 2017.[ permanent dead link ]
  29. ↑ "David Sabatini". National Academy of Sciences Member Directory. Retrieved 5 April 2017.
  30. ↑ "Past ASCB Officers". American Society for Cell Biology. Archived from the original on 7 April 2017. Retrieved 6 April 2017.
  31. ↑ "Keith R. Porter Lecture Award". American Society for Cell Biology. Retrieved 7 April 2017.
  32. ↑ "E.B. Wilson Medal". American Society for Cell Biology. Retrieved 7 April 2017.
  33. ↑ "APS Member History". search.amphilsoc.org. Retrieved 2021-07-13.
  34. ↑ Ware, Lauren (2013). "Science in their Blood". HHMI Bulletin. Howard Hughes Medical Institute. Retrieved 5 April 2017.
  35. ↑ Wadman, Meredith (2022). "Prominent biologist David Sabatini out at MIT after breaching sexual relationship policy". ScienceInsider. American Association for the Advancement of Science. Retrieved 25 April 2022.
  36. ↑ Weiss, Suzy (2022). "He Was a World-Renowned Cancer Researcher.Now He's Collecting Unemployment" . Retrieved 26 August 2022.
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