The HIV-1 Tat Protein Is Monomethylated at Lysine 71 by the Lysine Methyltransferase KMT7

Abstract

The HIV-1 transactivator protein Tat is a critical regulator of HIV transcription primarily enabling efficient elongation of viral transcripts. Its interactions with RNA and various host factors are regulated by ordered, transient post-translational modifications. Here, we report a novel Tat modification, monomethylation at lysine 71 (K71). We found that Lys-71 monomethylation (K71me) is catalyzed by KMT7, a methyltransferase that also targets lysine 51 (K51) in Tat. Using mass spectrometry, in vitro enzymology, and modification-specific antibodies, we found that KMT7 monomethylates both Lys-71 and Lys-51 in Tat. K71me is important for full Tat transactivation, as KMT7 knockdown impaired the transcriptional activity of wild type (WT) Tat but not a Tat K71R mutant. These findings underscore the role of KMT7 as an important monomethyltransferase regulating HIV transcription through Tat.

Hexacoordinated Tetrel‐Bonded Complexes between TF4 (T=Si, Ge, Sn, Pb) and NCH: Competition between σ‐ and π‐Holes

“…Closely related to these interactions are those in which the bridging atom comes from the tetrel family (C, Si, Ge, etc). [16][17][18][19][20][21] There is a rapidly growing literature [22][23][24][25][26][27] that has provided a wealth of insights into the chemical and physical phenomena that underlie tetrel bonds. This larger number of substituents obstructs a clear passage of an approaching nucleophile toward the tetrel atom, [8] which can inhibit the formation of such a bond or at the least require a good deal of deformation so as to clear a space for the Lewis base.…”

PJA2 ubiquitinates the HIV-1 Tat protein with atypical chain linkages to activate viral transcription

“…A series of acetyl transfer reactions control the RNA-binding activity of Tat, where acetylation of Lys28 by P300/CBP-associated factor (PCAF) increases the affinity of the Tat-Cyclin T1-TAR complex16 and acetylation of Lys50 by p300 disassembles this ternary complex17. Tat is also a substrate for methylation1819 and ubiquitination20.…”

Role of Host Factors on the Regulation of Tat-Mediated HIV-1 Transcription

“…Tat and P-TEFb post-translational modifications (PTMs) (acetylation, methylation, phosphorylation, polyubiquitination) play an important role in the regulation of TMT (reviewed in [3, 22, 23]). A recent study shows the importance of the lysine methyltransferase 7 (KMT7), encoded by the SET domain containing KMT7 gene, to facilitate TAR/Tat/P-TEFb complex formation and to increase TMT [24]. KMT7 binds TAR and monomethylates Tat at position Lys51 and Lys71, PTMs suggested to improve Tat’s affinity for TAR [24, 25].…”

“…A recent study shows the importance of the lysine methyltransferase 7 (KMT7), encoded by the SET domain containing KMT7 gene, to facilitate TAR/Tat/P-TEFb complex formation and to increase TMT [24]. KMT7 binds TAR and monomethylates Tat at position Lys51 and Lys71, PTMs suggested to improve Tat’s affinity for TAR [24, 25]. The combination of Lys51Arg and Lys71Arg mutations almost completely abolish TMT [24].…”

“…KMT7 binds TAR and monomethylates Tat at position Lys51 and Lys71, PTMs suggested to improve Tat’s affinity for TAR [24, 25]. The combination of Lys51Arg and Lys71Arg mutations almost completely abolish TMT [24]. Moreover, numerous studies have demonstrated the importance of the super elongation complex (SEC) to act in concert with the TAR/Tat/P-TEFb axis to promote TMT [26–28].…”