On the Nature of Allosteric Transitions: A Plausible Model

In 1901 a physician, Archibald Garrod, observed a patient with black urine. He used this simple observation to demonstrate that a single mutant gene can produce a discrete block in a biochemical pathway, which he called an “inborn error of metabolism”. Garrod’s brilliant insight anticipated by 40 years the one gene-one enzyme concept of Beadle and Tatum. In similar fashion the chemist Linus Pauling and the biochemist Vernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1). We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia or FH. In these patients the concentration of cholesterol in blood is elevated many fold above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw light on fundamental regulatory mechanisms. Our approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH. These studies led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis (2,3). FH was shown to be caused by inherited defects in the gene encoding the LDL receptor, which disrupt the normal control of cholesterol metabolism. Study of the LDL receptor in turn led to the understanding of receptor-mediated endocytosis, a genera! process by which cells communicate with each other through internalization of regulatory and nutritional molecules (4). Receptor-mediated endocytosis differs from previously described biochemical pathways because it depends upon the continuous and highly controlled movement of membraneembedded proteins from one cell organelle to another in a process termed

https://science.sciencemag.org/content/sci/232/4746/34.full.pdf

A receptor-mediated pathway for cholesterol homeostasis.

In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The following recommendations were endorsed at the workshop. (a) The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called microsatellite instability (MSI). (b) A panel of five microsatellites has been validated and is recommended as a reference panel for future research in the field. Tumors may be characterized on the basis of: high-frequency MSI (MSI-H), if two or more of the five markers show instability (i.e., have insertion/deletion mutations), and low-frequency MSI (MSI-L), if only one of the five markers shows instability. The distinction between microsatellite stable (MSS) and low frequency MSI (MSI-L) can only be accomplished if a greater number of markers is utilized. (c) A unique clinical and pathological phenotype is identified for the MSI-H tumors, which comprise approximately 15% of colorectal cancers, whereas MSI-L and MSS tumors appear to be phenotypically similar. MSI-H colorectal tumors are found predominantly in the proximal colon, have unique histopathological features, and are associated with a less aggressive clinical course than are stage-matched MSI-L or MSS tumors. Preclinical models suggest the possibility that these tumors may be resistant to the cytotoxicity induced by certain chemotherapeutic agents. The implications for MSI-L are not yet clear. (d) MSI can be measured in fresh or fixed tumor specimens equally well; microdissection of pathological specimens is recommended to enrich for neoplastic tissue; and normal tissue is required to document the presence of MSI. (e) The "Bethesda guidelines," which were developed in 1996 to assist in the selection of tumors for microsatellite analysis, are endorsed. (f) The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms. (g) A research agenda was recommended.

https://cancerres.aacrjournals.org/content/canres/58/22/5248.full.pdf

A National Cancer Institute Workshop on Microsatellite Instability for Cancer Detection and Familial Predisposition: Development of International Criteria for the Determination of Microsatellite Instability in Colorectal Cancer

The t(14; 18) chromosomal translocation of human follicular B-cell lymphoma juxtaposes the bcl-2 gene with the immunoglobulin heavy chain locus. The bcl-2 immunoglobulin fusion gene is markedly deregulated resulting in inappropriately elevated levels of bcl-2 RNA and protein. Transgenic mice bearing a bcl-2 immunoglobulin minigene demonstrate a polyclonal expansion of resting yet responsive IgM-IgD B cells which display prolonged cell survival but no increase in cell cycling. Moreover, deregulated bcl-2 extends the survival of certain haematopoietic cell lines following growth-factor deprivation. By using immunolocalization studies we now demonstrate that Bcl-2 is an integral inner mitochondrial membrane protein of relative molecular mass 25,000 (25k). Overexpression of Bcl-2 blocks the apoptotic death of a pro-B-lymphocyte cell line. Thus, Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and interfering with programmed cell death independent of promoting cell division.

Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death

https://www.cell.com/cell/pdf/0092-8674(92)90189-J.pdf

Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface

PERSPECTIVES AND SUMMARY 631 STRUCTURES OF ASPARAGINE-LINKED OLIGOSACCI-IARIDES 632 ASSEMBLY AND TRANSFER OF THE LIPID-LINKED OLIGOSACCHARIDE ...... 635 Assembly 635 Transfer-Oligosaccharide Structural Requirements 636 Transfer-Role of Peptide Acceptor 637 OLIGOSACCHARIDE P OCESSING 639 Sequence of Processing 639 Subcellular Localization of Processing Enzymes 641 Processing in Lower Organisms 643 Specificity of Processing Enzymes 644 OTHER POS’VI~RANSLATIONAL MODIFICATIONS 653 CONTROL F OLIGOSACCHARIDE PROCESSING 655

/pdf/assembly-of-asparagine-linked-oligosaccharides-fv8c1crug7.pdf

Assembly of asparagine-linked oligosaccharides.

Article de synthese sur les lysosomes: biogenese, definition, role biologique. Les enzymes lysosomales sont decrites ainsi que leur role dans l'exo et l'endocytose. La structure et le biogenese de la membrane lysosomale sont etudiees

The Biogenesis of Lysosomes

PERSPECTIVES AND SUMMARY ... .... . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... 308 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 RECEPTOR STRUCTURE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Prima ry Structure and Genomic Organization....... . . . . . . . .. . . . . . . . . . . . . . . . . . .... . . . . . . ... 309 Oligomeric Structure .. . . . . . . . . .. .. .. .. ...... . . . . . .. . .. ..... . . . . . .... 311 Ligand-Binding P roperties . . . .. . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . .. . 312 RECEPTOR FUNCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . 314 Role in Lysosomal Enzyme Sorting and Endocytosis . . . . .. . . . . . . . . .. ... ...... 314 Role in Signal Transduction ... . .. . . . . . . . . . . . . . . . . . . . . . . . . .. ...... . . .... ..... ... . . . . . . . ... .. . . . . 314 Role in Hormone Clearance and Activation. . . . . . . . .... . . .. . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 317 Role in Extracellular Matrix Degradation ... . . . . . . . . . . . . . . . 317 RECEPTOR DISTRIBUTION AND TRAFFICKING . . . . . . .. ... ....... . . . . . . . . . . . ... . . . . . . . . . 318 Subcellular Localization....... ......... . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . ..... 318 Regulation of Receptor Trafficking . . . . . . . . . . .. .... ... . . . . . . . . . . . . . . . . . . 319 S tructural Determinants of Receptor Traffickin g . . . . . . . . . . . . . . . . . . . . .. . . . ...... 320 Reconstitution of Receptor Trafficking in Cell Extracts . . . . . . . . . . . ..... . . . . . . . . . . ... . . . . . . 323 DEVELOPMENTAL REGULATION AND TISSUE-SPECIFIC EXPRESSION . . . . . . . . . 324

Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors.

The two mannose 6-phosphate (M6P) receptors were identified because of their ability to bind M6P-containing soluble acid hydrolases in the Golgi and transport them to the endosomal-lysosomal system. During the past decade, we have started to understand the structural features of these receptors that allow them to do this job, and how the receptors themselves are sorted as they pass through various membrane-bound compartments. But trafficking of acid hydrolases is only part of the story. Evidence is emerging that one of the receptors can regulate cell growth and motility, and that it functions as a tumour suppressor.

https://ressources.unisciel.fr/biocell/chap9/res/07_17_Mannose6P_Receptor_Review_Ghosh-Kornfeld.pdf

Stuart Kornfeld

Papers

Assembly of asparagine-linked oligosaccharides.

The Biogenesis of Lysosomes

Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors.

Mannose 6-phosphate receptors: new twists in the tale

The mannose 6-phosphate receptor and the biogenesis of lysosomes