The beta subunit of voltage-gated Ca2+ channels interacts with and regulates the activity of a novel isoform of Pax6.
Ca(2+) channel beta subunits (Ca(v)betas) are essential for regulating the surface expression and gating of high voltage-activated Ca(2+) channels through their interaction with Ca(2+) channel alpha(1) subunits. In efforts to uncover new interacting partners and new functions for Ca(v)beta, we identified a new splicing isoform of Pax6, a transcription factor crucial for the development of the eye, nose, brain, and pancreas. Pax6 contains two DNA binding domains (paired domain and homeodomain), a glycine-rich linker connecting these two domains and a C-terminal proline-, serine-, and threonine-rich transactivation domain. The protein sequence and function of Pax6 are highly conserved from invertebrate to human. The newly isolated isoform, named Pax6(S), retains the paired domain, linker, and homeodomain of Pax6, but its C terminus is composed of a truncated classic proline, serine, and threonine domain and a unique S tail. Pax6(S) shows a similar level of transcriptional activity in vitro as does Pax6, but only in primates is the protein sequence highly conserved. Its spatial-temporal expression profiles are also different from those of Pax6. These divergences suggest a noncanonical role of Pax6(S) during development. The interaction between Pax6(S) and Ca(v)beta is mainly endowed by the S tail. Co-expression of Pax6(S) with a Ca(2+) channel complex containing the beta(3) subunit in Xenopus oocytes does not affect channel properties. Conversely, however, beta(3) is able to suppress the transcriptional activity of Pax6(S). Furthermore, in the presence of Pax6(S), beta(3) is translocated from the cytoplasm to the nucleus. These results suggest that full-length Ca(v)beta may act directly as a transcription regulator independent of its role in regulating Ca(2+) channel activity.
Zhang
Yun
Y
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Yamada
Yoichi
Y
Fan
Mingming
M
Bangaru
Saroja D
SD
Lin
Bochao
B
Yang
Jian
J
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001703:Biophysics; D016466:CHO Cells; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000378:metabolism; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*; D014982:Xenopus laevis
C096073:CACNB3 protein, human; D015220:Calcium Channels; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D021122:Protein Subunits; D012097:Repressor Proteins