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J. Biol. Chem., Vol. 276, Issue 18, 14710-14717, May 4, 2001
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From the Department of Chemistry and Biochemistry, New Mexico State
University, Las Cruces, New Mexico 88003
Retroviral integrases (INs) interact with termini
of retroviral DNA in the conserved 5'-C(A/G)T. For most integrases,
modifications of critical moieties in the major and minor grooves of
these sequences decrease 3'-processing. However, for human
immunodeficiency virus type-2 (HTLV-2) IN, the replacement of the
guanine with 6-methylguanine or hypoxanthine not only reduced
3'-processing, but also promoted cleavage at a second site. This novel
cleavage activity required an upstream ACA, unique to the HTLV-2 U5
end. 3'-Processing assays with additional isosteric modifications at
Gua and filter binding experiments revealed that the mechanism of the
second site cleavage differed among the major groove, minor groove, and
mismatch modifications. Importantly, the decrease in 3'-processing
activity noted with the minor groove and mismatch modifications were
attributed to a decrease in binding. Major groove modifications,
however, decreased the level of 3'-processing, but did not affect
binding. This suggests that integrase binds the viral end through the
minor groove, but relies on major groove contacts for 3'-processing.
Several modifications were also examined in strand transfer and
disintegration substrates. HTLV-2 IN showed reduced activity with
strand transfer and disintegration substrates containing major groove,
but not minor groove modifications. This suggests major groove
interactions at guanine also provide an important role in these reactions.
Interactions of the Human T-cell Leukemia Virus Type-II
Integrase with the Conserved CA in the Retroviral Long Terminal
Repeat End*
§,¶, and
*
This work was supported by National Institutes of Health
Grant R15CA74398-01 (to C. B. J.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Contributed equally to the results of this work.
§
Present address: 1650 Lincoln, number 1106, Montreal, QC, H3H 1H1 Canada.
¶
Present address: Dept. of Chemistry and Biochemistry, Box
30001, MSC 3C, New Mexico State University, Las Cruces, NM 88003.
To whom correspondence should be addressed: Dept. of Chemistry
and Biochemistry, New Mexico State University, Box 30001, MSC 3C, Las
Cruces, NM 88003. Tel.: 505-646-3346; Fax: 505-646-2649; E-mail:
cjonsson@nmsu.edu.
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