Differential functions of the two Src homology 2 domains in protein tyrosine phosphatase SH-PTP1.

SH-PTP1 (also known as PTP1C, HCP, and SHP) is a non-transmembrane protein tyrosine phosphatase (PTPase) containing two tandem Src homology 2 (SH2) domains. We show here that the two SH2 (N-SH2 and C-SH2) domains in SH-PTP1 have different functions in regulation of the PTPase domain and thereby signal transduction. While the N-terminal SH2 domain is both necessary and sufficient for autoinhibition through an intramolecular association with the PTPase domain, truncation of the C-SH2 domain [SH-PTP1 (delta CSH2) construct] has little effect on SH-PTP1 activity. A synthetic phosphotyrosine residue (pY) peptide derived from the erythropoietin receptor (EpoR pY429) binds to the N-SH2 domain and activates both wild-type SH-PTP1 and SH-PTP1 (delta CSH2) 60- to 80-fold. Another pY peptide corresponding to a phosphorylation site on the IgG Fc receptor (Fc gamma RIIB1 pY309) associates with both the C-SH2 domain (Kd = 2.8 microM and the N-SH2 domain (Kd = 15.0 microM) and also activates SH-PTP1 12-fold. By analysis of the effect of the Fc gamma RIIB1 pY309 peptide on SH-PTP1 (delta CSH2), SH-PTP1 (R30K/R33E), SH-PTP1 (R30K/R136K), and SH-PTP1 (R136K) mutants in which the function of either the N- or C-SH2 domain has been impaired, we have determined that both synthetic pY peptides stimulate SH-PTP1 by binding to its N-SH2 domain; binding of pY ligand to the C-SH2 domain has no effect on SH-PTP1 activity. We propose that the N-terminal SH2 domain serves both as a regulatory domain and as a recruiting unit, whereas the C-terminal SH2 domain acts merely as a recruiting unit.

The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction.

Quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.2], also called DT diaphorase, is a homodimeric FAD-containing enzyme that catalyzes obligatory NAD(P)H-dependent two-electron reductions of quinones and protects cells against the toxic and neoplastic effects of free radicals and reactive oxygen species arising from one-electron reductions. These two-electron reductions participate in the reductive bioactivation of cancer chemotherapeutic agents such as mitomycin C in tumor cells. Thus, surprisingly, the same enzymatic reaction that protects normal cells activates cytotoxic drugs used in cancer chemotherapy. The 2.1-A crystal structure of rat liver quinone reductase reveals that the folding of a portion of each monomer is similar to that of flavodoxin, a bacterial FMN-containing protein. Two additional portions of the polypeptide chains are involved in dimerization and in formation of the two identical catalytic sites to which both monomers contribute. The crystallographic structures of two FAD-containing enzyme complexes (one containing NADP+, the other containing duroquinone) suggest that direct hydride transfers from NAD(P)H to FAD and from FADH2 to the quinone [which occupies the site vacated by NAD(P)H] provide a simple rationale for the obligatory two-electron reductions involving a ping-pong mechanism.

Deliciae Britannicae, or, The curiosities of Hampton-Court and Windsor-Castle, delineated : with occasional reflections, and embellish'd with copper-plates of the two palaces, &c. /

Head and tail-pieces.

Remarks at the commemoration ceremony in honor of the two-hundredth anniversary of the First Continental Congress /

Mode of access: Internet.

Path integral calculation of the two-particle slater sum for He4 /

"August 20, 1965"

Picturesque Stamford : a souvenir of the two hundred and fiftieth anniversary of the settlement of the town of Stamford, containing an historical sketch, covering salient points of Stamford's history from 1641 to 1892, together with special chapters on its churches, schools, societies, clubs, commercial, manufacturing and financial institutions, mercantile houses and affairs, etc. /

At head of title: 1641--1892.

Misalignment and quadrupole error problems affecting the choice of multiplet type for sector focusing of the two-mile accelerator /

"AEC Contract AT(04-3)-400."

A metrical history of England; or, Recollections, in rhyme, of some of the most prominent features in our national chronology, from the landing of Julius Cæsar, to the commencement of the regency, in 1812 ...

Mode of access: Internet.

Life and ways of the two-year-old, a teacher's study,

Mode of access: Internet.

Manual, containing the rules of the Senate and House of Representatives, of the state of Michigan and joint rules of the two houses and other matter.

Some vols. include the Constitution of the state.

List of members, officers and committees and the rules of the two houses.

Mode of access: Internet.

List of members, officers, committees and attaches and the rules of the two houses of the California Legislature.

Mode of access: Internet.

Address to the veterans of the Mexican war. Embodying a historical contrast of the two great political parties of the United States on vital issues, with personal reminiscences and other pertinent episodes. Also: an appendix of three chapters, entitled "The California democratic state club pilloried."--"A new plundercrat organ disguised in the garb of democracy."--"To the greenback-labor voters."

Mode of access: Internet.