TY - JOUR
T1 - Functional regulation of the SLC26-family protein prestin by calcium/calmodulin
AU - Keller, Jacob Pearson
AU - Homma, Kazuaki
AU - Duan, Chongwen
AU - Zheng, Jing
AU - Cheatham, Mary Ann
AU - Dallos, Peter
PY - 2014
Y1 - 2014
N2 - The solute carrier gene family 26 (SLC26) encodes membrane proteins with diverse physiological roles but with the common feature of halide involvement. Here, we present bioinformatic and biochemical evidence that SLC26 proteins have intrinsically disordered regions (IDRs) in their C-terminal domains and that these regions contain calmodulin (CaM) binding sites. The veracity of these predictions and the functional consequences of CaM binding were examined in prestin, SLC26A5, as a model for the SLC26 family and as one of the most investigated and best understood members. We found that CaM binds directly to the IDR in the C-terminal domain of prestin in a calcium-obligate manner. Using both isolated murine outer hair cells (OHCs) and a heterologous expression system, we also found that this calcium-obligate CaM binding shifts the operating point of the protein to more hyperpolarized potentials with consequent alteration of the function of the prestin. Because calcium is the main intracellular second messenger used by the efferent medial olivocochlear (MOC) pathway of the auditory system andCaMis abundant in OHCs, the CaM-prestin interactionmaybe involved in the MOC-mediated modulation of cochlear amplification. However, this regulatory mechanism is not likely to be restricted to cochlear OHCs, in light of both clear bioinformatic evidence and the fact that calcium and CaM are ubiquitous intracellular second messengers used by virtually all cell types. Hence, the calcium/CaM-dependent regulatory mechanism described herein is likely applicable to most, if not all, SLC26 paralogs.
AB - The solute carrier gene family 26 (SLC26) encodes membrane proteins with diverse physiological roles but with the common feature of halide involvement. Here, we present bioinformatic and biochemical evidence that SLC26 proteins have intrinsically disordered regions (IDRs) in their C-terminal domains and that these regions contain calmodulin (CaM) binding sites. The veracity of these predictions and the functional consequences of CaM binding were examined in prestin, SLC26A5, as a model for the SLC26 family and as one of the most investigated and best understood members. We found that CaM binds directly to the IDR in the C-terminal domain of prestin in a calcium-obligate manner. Using both isolated murine outer hair cells (OHCs) and a heterologous expression system, we also found that this calcium-obligate CaM binding shifts the operating point of the protein to more hyperpolarized potentials with consequent alteration of the function of the prestin. Because calcium is the main intracellular second messenger used by the efferent medial olivocochlear (MOC) pathway of the auditory system andCaMis abundant in OHCs, the CaM-prestin interactionmaybe involved in the MOC-mediated modulation of cochlear amplification. However, this regulatory mechanism is not likely to be restricted to cochlear OHCs, in light of both clear bioinformatic evidence and the fact that calcium and CaM are ubiquitous intracellular second messengers used by virtually all cell types. Hence, the calcium/CaM-dependent regulatory mechanism described herein is likely applicable to most, if not all, SLC26 paralogs.
KW - Calmodulin
KW - Disordered region
KW - Mice
KW - Prestin
KW - SLC26 family
UR - http://www.scopus.com/inward/record.url?scp=84892771506&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892771506&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4020-13.2014
DO - 10.1523/JNEUROSCI.4020-13.2014
M3 - Article
C2 - 24453323
AN - SCOPUS:84892771506
SN - 0270-6474
VL - 34
SP - 1325
EP - 1332
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 4
ER -