ABCD proteins

April 15th, 2016 |

Stephan Kemp, Ph.D.

The ABC protein family

ATP-binding cassette (ABC) proteins form the largest family of transmembrane proteins. They are pumps that move substrates in (influx) or out (efflux) of cells. ABC transporters have important physiological functions in all living organisms. They are present in all prokaryotes, as well as plants, fungi, yeast and animals. The human genome contains 49 ABC genes. In mammals, ABC transporters are expressed predominantly in the liver, intestine, blood-brain barrier, blood-testis barrier, placenta and kidney. ABC transporters bind and hydrolyze ATP and use the energy of this reaction to drive the transport of various molecules across cellular membranes, often against steep concentration gradients.

The typical structure of an ABC transporter is composed of two transmembrane domains (TMD) and two nucleotide binding domains (NBD). There are several different arrangements of the TMD and NBD domains found among the human ABC proteins. But in general, a full functional transporter is build up following the TMD-NBD-TMD-NBD composition. The four domains may be present in one polypeptide (like the MDR P-glycoproteins), or they can be formed by dimerization of two ABC half-transporters, TAP1 (ABCB2) and TAP2 (ABCB3). The two NBD domains bind and hydrolyze ATP, which provides the driving force for transport. The two TMDs participate in substrate recognition and translocation across the membrane. ALDP is a half-transporter that must dimerize with another half-transporter to form a full-transporter.

Schematic structure of the ABC half-transporters and full-transporters. The nucleotide binding domain (NBD) and Pex19p binding site (*) are indicated.

Schematic structure of the ABC half-transporters and full-transporters.

The peroxisomal ABC transporters (ABCD)

The peroxisomal ABC half-transporters ALDP (ABCD1), adrenoleukodystrophy-related protein (ALDRP, ABCD2)) and the 70 kDa peroxisomal membrane protein (PMP70, ABCD3) form a separate subclass of the ABC proteins (subclass D). PMP69 (or P70R, ABCD4) is the fourth member of the ABCD family. While ABCD4 was originally identified as a peroxisomal protein, recent studies have suggested its localization to the endoplasmic reticulum or within the lysosome. ABCD4 has significant amino acid identity (25–27%) with ABCD1, 2 and 3, but it lacks the peptide signal necessary for localization to the peroxisome. Recent research demonstrated that ABCD4 is associated with lysosomes and has an important role in vitamin B12 metabolism.

protein gene name Cellular localization chromosomal location
ALDP ABCD1 peroxisomal Xq28
ALDRP ABCD2 peroxisomal 12q11
PMP70 ABCD3 peroxisomal 1p21-22
PMP69 or P70R ABCD4 lysosome 14q24.3

Alignment peroxisomal ABCD proteins

ABCD1           ----MPVLSRPRPWRGNTLKRTAVLLALAAYGAHKVYPLVRQCLAP-ARGLQAPAGEPTQ 55
ABCD2           MTHMLNAAADRVKWTRSSAAKRAACLVAAAYALKTLYPIIGKRLKQSGHGKKKAAAYPAA 60
ABCD3           ----MAAFSKYLTARNSSLAGAAFLLLCLLHKRRRALGLHGK-----------KSGKPPL 45
                    : . :       .:    *  *    :  :    :  :            :. *. 

ABCD1           EASGVAAAKA--------GMNRVFLQRLLWLLRLLFPRVLCRETGLLALHSAALVSRTFL 107
ABCD2           ENTEILHCTETICEKPSPGVNADFFKQLLELRKILFPKLVTTETGWLCLHSVALISRTFL 120
ABCD3           QNNEKEGKKER------AVVDKVFFSRLIQILKIMVPRTFCKETGYLVLIAVMLVSRTYC 99
                : .     .          ::  *:.:*: : :::.*: .  *** * * :. *:***: 

ABCD1           SVYVARLDGRLARCIVRKDPRAFGWQLLQWLLIALPATFVNSAIRYLEGQLALSFRSRLV 167
ABCD2           SIYVAGLDGKIVKSIVEKKPRTFIIKLIKWLMIAIPATFVNSAIRYLECKLALAFRTRLV 180
ABCD3           DVWMIQNGTLIESGIIGRSRKDFKRYLLNFIAAMPLISLVNNFLKYGLNELKLCFRVRLT 159
                .:::   .  :   *: :. : *   *::::      ::**. ::*   :* *.** **.

ABCD1           AHAYRLYFSQQTYYRVSNMDGRLRNPDQSLTEDVVAFAASVAHLYSNLTKPLLDVAVTSY 227
ABCD2           DHAYETYFTNQTYYKVINMDGRLANPDQSLTEDIMMFSQSVAHLYSNLTKPILDVMLTSY 240
ABCD3           KYLYEEYLQAFTYYKMGNLDNRIANPDQLLTQDVEKFCNSVVDLYSNLSKPFLDIVLYIF 219
                 : *. *:   ***:: *:*.*: **** **:*:  *. **..*****:**:**: :  :

ABCD1           TLLRAARSRGAGTAWPSAIAGLVVFLTANVLRAFSPKFGELVAEEARRKGELRYMHSRVV 287
ABCD2           TLIQTATSRGASPIGPTLLAGLVVYATAKVLKACSPKFGKLVAEEAHRKGYLRYVHSRII 300
ABCD3           KLTSAIGAQGP----ASMMAYLVVSG--LFLTRLRRPIGKMTITEQKYEGEYRYVNSRLI 273
                .*  :  ::*.    .: :* ***     .*      :*::.  * : :*  **::**::

ABCD1           ANSEEIAFYGGHEVELALLQRSYQDLASQINLILLERLWYVMLEQFLMKYVWSASGLLMV 347
ABCD2           ANVEEIAFYRGHKVEMKQLQKSYKALADQMNLILSKRLWYIMIEQFLMKYVWSSSGLIMV 360
ABCD3           TNSEEIAFYNGNKREKQTVHSVFRKLVEHLHNFILFRFSMGFIDSIIAKYLATVVGYLVV 333
                :* ****** *:: *   ::  :: *..::: ::  *:   :::.:: **: :  * ::*

ABCD1           AVPIITATGYSESDAEAVKKAALEKKEEELVSERTEAFTIARNLLTAAADAIERIMSSYK 407
ABCD2           AIPIITATGFADGE---------DGQKQVMVSERTEAFTTARNLLASGADAIERIMSSYK 411
ABCD3           SRPFLDLS--------------HPRHLKSTHSELLEDYYQSGRMLLRMSQALGRIVLAGR 379
                : *::  :                 : :   **  * :  : .:*   ::*: **: : :

ABCD1           EVTELAGYTARVHEMFQVFEDVQRCHFKRPRELEDAQAGSGTIGRSGVRVEGPLKIRGQV 467
ABCD2           EVTELAGYTARVYNMFWVFDEVKRGIYKRTAVIQESESHSKNGAKVELPLSDTLAIKGKV 471
ABCD3           EMTRLAGFTARITELMQVLKDLNHGKYERTMVSQQEK------GIEGVQVIPLIPGAGEI 433
                *:*.***:***: ::: *:.::::  ::*.   :: :      .   : :   :   *::

ABCD1           VDVEQGIICENIPIVTPSGEVVVASLNIRVEEGMHLLITGPNGCGKSSLFRILGGLWPTY 527
ABCD2           IDVDHGIICENVPIITPAGEVVASRLNFKVEEGMHLLITGPNGCGKSSLFRILSGLWPVY 531
ABCD3           IIADNIIKFDHVPLATPNGDVLIRDLNFEVRSGANVLICGPNGCGKSSLFRVLGELWPLF 493
                : .:: *  :::*: ** *:*:   **:.*..* ::** ************:*. *** :

ABCD1           GGVLYKPPPQRMFYIPQRPYMSVGSLRDQVIYPDSVEDMQRKGYSEQDLEAILDVVHLHH 587
ABCD2           EGVLYKPPPQHMFYIPQRPYMSLGSLRDQVIYPDSVDDMHDKGYTDQDLERILHNVHLYH 591
ABCD3           GGRLTKPERGKLFYVPQRPYMTLGTLRDQVIYPDGREDQKRKGISDLVLKEYLDNVQLGH 553
                 * * **   ::**:******::*:*********. :* : ** ::  *:  *. *:* *

ABCD1           ILQREGGWEAMCDWKDVLSGGEKQRIGMARMFYHRPKYALLDECTSAVSIDVEGKIFQAA 647
ABCD2           IVQREGGWDAVMDWKDVLSGGEKQRMGMARMFYHKPKYALLDECTSAVSIDVEGKIFQAA 651
ABCD3           ILEREGGWDSVQDWMDVLSGGEKQRMAMARLFYHKPQFAILDECTSAVSVDVEGYIYSHC 613
                *::*****::: ** **********:.***:***:*::*:*********:**** *:. .

ABCD1           KDAGIALLSITHRPSLWKYHTHLLQFDGEGGWKFEKLDSAARLSLTEEKQRLEQQLAGIP 707
ABCD2           KGAGISLLSITHRPSLWKYHTHLLQFDGEGGWRFEQLDTAIRLTLSEEKQKLESQLAGIP 711
ABCD3           RKVGITLFTVSHRKSLWKHHEYYLHMDGRGNYEFKQIT--------EDTVEFGS------ 659
                : .**:*::::** ****:* : *::**.*.:.*:::         *:. .: .      

ABCD1           KMQRRLQELCQILGEAVAPAHVPAPSPQGPGGLQGAST 745
ABCD2           KMQQRLNELCKILGEDSVLKTIKNEDETS--------- 740
ABCD3           --------------------------------------

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