Journal of Bioenergetics and Biomembranes

, Volume 48, Issue 3, pp 259–267 | Cite as

New insights into the roles of the N-terminal region of the ABCC6 transporter

  • Rocchina Miglionico
  • Andrea Gerbino
  • Angela Ostuni
  • Maria Francesca Armentano
  • Magnus Monné
  • Monica Carmosino
  • Faustino Bisaccia


ABCC6 is a human ATP binding cassette (ABC) transporter of the plasma membrane associated with Pseudoxanthoma elasticum (PXE), an autosomal recessive disease characterized by ectopic calcification of elastic fibers in dermal, ocular and vascular tissues. Similar to other ABC transporters, ABCC6 encloses the core structure of four domains: two transmembrane domains (TMDs) and two nucleotide binding domains (NBDs) but also an additional N-terminal extension, including a transmembrane domain (TMD0) and a cytosolic loop (L0), which is only found in some members of ABCC subfamily, and for which the function remains to be established. To investigate the functional roles of this N-terminal region, we generated several domain deletion constructs of ABCC6, expressed in HEK293 and polarized LLC-PK1 cells. ABCC6 lacking TMD0 displayed full transport activity as the wild type protein. Unlike the wild type protein, ABCC6 without L0 was not targeted to the basolateral membrane. Moreover, homology modeling of L0 suggests that it forms an ATPase regulatory domain. Furthermore, we show that the expression of ABCC6 is linked to a cellular influx of Ca2+. The results suggest that TMD0 is not required for transport function and that L0 maintains ABCC6 in a targeting-competent state for the basolateral membrane and might be involved in regulating the NBDs. These findings shed new light on a possible physiological function of ABCC6 and may explain some of the hallmarks of the clinical features associated with PXE that could contribute to the identification of novel pharmacological targets.


ABCC6 PXE TMD0 Ca2+ channel 



ATP binding cassette


endoplasmic reticulum


nucleotide binding domain




pseudoxanthoma elasticum


sulfonylurea-binding receptor


transmembrane domain

Supplementary material

10863_2016_9654_MOESM1_ESM.pdf (2.6 mb)
ESM 1(PDF 2.55 mb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Rocchina Miglionico
    • 1
  • Andrea Gerbino
    • 2
  • Angela Ostuni
    • 1
  • Maria Francesca Armentano
    • 1
  • Magnus Monné
    • 1
  • Monica Carmosino
    • 1
  • Faustino Bisaccia
    • 1
  1. 1.Department of SciencesUniversity of BasilicataPotenzaItaly
  2. 2.Department of Biosciences, Biotechnology and BiopharmaceuticsUniversity of BariBariItaly

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