APC Family

{{Pfam_box

| Symbol = APC

| Name =

| image =

| width =

| caption =

| Pfam = PF00324

| Pfam_clan =

| InterPro = IPR004841

| SMART =

| PROSITE =

| SCOP =

| TCDB = 2.A.3

| OPM family = 64

| OPM protein = 3gia

| PDB =

}}

The Amino Acid-Polyamine-Organocation (APC) Family (TC# 2.A.3) of transport proteins includes members that function as solute:cation symporters and solute:solute antiporters.{{cite journal | vauthors = Saier MH | title = Families of transmembrane transporters selective for amino acids and their derivatives | journal = Microbiology | volume = 146 ( Pt 8) | issue = 8 | pages = 1775–95 | date = August 2000 | pmid = 10931885 | doi = 10.1099/00221287-146-8-1775 | doi-access = free }}{{cite journal | vauthors = Wong FH, Chen JS, Reddy V, Day JL, Shlykov MA, Wakabayashi ST, Saier MH | title = The amino acid-polyamine-organocation superfamily | journal = Journal of Molecular Microbiology and Biotechnology | volume = 22 | issue = 2 | pages = 105–13 | date = 2012 | pmid = 22627175 | doi = 10.1159/000338542 | doi-access = free }}{{cite book | vauthors = Schweikhard ES, Ziegler CM | title = Amino acid secondary transporters: toward a common transport mechanism | journal = Current Topics in Membranes | volume = 70 | pages = 1–28 | date = 2012 | pmid = 23177982 | doi = 10.1016/B978-0-12-394316-3.00001-6 | isbn = 9780123943163 }}{{cite journal | vauthors = Perland E, Fredriksson R | title = Classification Systems of Secondary Active Transporters | journal = Trends in Pharmacological Sciences | volume = 38 | issue = 3 | pages = 305–315 | date = March 2017 | pmid = 27939446 | doi = 10.1016/j.tips.2016.11.008 }} They occur in bacteria, archaea, fungi, unicellular eukaryotic protists, slime molds, plants and animals. They vary in length, being as small as 350 residues and as large as 850 residues. The smaller proteins are generally of prokaryotic origin while the larger ones are of eukaryotic origin. Most of them possess twelve transmembrane α-helical spanners but have a re-entrant loop involving TMSs 2 and 3.{{cite journal | vauthors = Gasol E, Jiménez-Vidal M, Chillarón J, Zorzano A, Palacín M | title = Membrane topology of system xc- light subunit reveals a re-entrant loop with substrate-restricted accessibility | journal = The Journal of Biological Chemistry | volume = 279 | issue = 30 | pages = 31228–36 | date = July 2004 | pmid = 15151999 | doi = 10.1074/jbc.M402428200 | doi-access = free }}{{cite web|last1=Saier|first1=MH Jr.|title=2.A.3 The Amino Acid-Polyamine-Organocation (APC) Superfamily|url=http://www.tcdb.org/search/result.php?tc=2.A.3|website=Transporter Classification Database|publisher=Saier Lab Bioinformatics Group / SDSC}} The APC Superfamily was established to encompass a wider range of homologues.

Members of APC Family

Members of one subfamily within the APC family (SGP; TC# 2.A.3.9) are amino acid receptors rather than transporters {{cite journal | vauthors = Cabrera-Martinez RM, Tovar-Rojo F, Vepachedu VR, Setlow P | title = Effects of overexpression of nutrient receptors on germination of spores of Bacillus subtilis | journal = Journal of Bacteriology | volume = 185 | issue = 8 | pages = 2457–64 | date = April 2003 | pmid = 12670969 | pmc = 152624 | doi = 10.1128/jb.185.8.2457-2464.2003 }} and are truncated at their C-termini, relative to the transporters, having 10 TMSs.{{cite journal | vauthors = Jack DL, Paulsen IT, Saier MH | title = The amino acid/polyamine/organocation (APC) superfamily of transporters specific for amino acids, polyamines and organocations | journal = Microbiology | volume = 146 ( Pt 8) | issue = 8 | pages = 1797–814 | date = August 2000 | pmid = 10931886 | doi = 10.1099/00221287-146-8-1797 | doi-access = free }}

The eukaryotic members of another subfamily (CAT; TC# 2.A.3.3) and the members of a prokaryotic subfamily (AGT; TC #2.A.3.11) have 14 TMSs.{{cite journal | vauthors = Lorca G, Winnen B, Saier MH | title = Identification of the L-aspartate transporter in Bacillus subtilis | journal = Journal of Bacteriology | volume = 185 | issue = 10 | pages = 3218–22 | date = May 2003 | pmid = 12730183 | pmc = 154055 | doi = 10.1128/jb.185.10.3218-3222.2003 }}

The larger eukaryotic and archaeal proteins possess N- and C-terminal hydrophilic extensions. Some animal proteins, for example, those in the LAT subfamily (TC# 2.A.3.8) including ASUR4 (gbY12716) and SPRM1 (gbL25068) associate with a type 1 transmembrane glycoprotein that is essential for insertion or activity of the permease and forms a disulfide bridge with it. These glycoproteins include the CD98 heavy chain protein of Mus musculus (gbU25708) and the orthologous 4F2 cell surface antigen heavy chain of Homo sapiens (spP08195). The latter protein is required for the activity of the cystine/glutamate antiporter (2.A.3.8.5), which maintains cellular redox balance and cysteine/glutathione levels.{{cite journal | vauthors = Sato H, Shiiya A, Kimata M, Maebara K, Tamba M, Sakakura Y, Makino N, Sugiyama F, Yagami K, Moriguchi T, Takahashi S, Bannai S | title = Redox imbalance in cystine/glutamate transporter-deficient mice | journal = The Journal of Biological Chemistry | volume = 280 | issue = 45 | pages = 37423–9 | date = November 2005 | pmid = 16144837 | doi = 10.1074/jbc.m506439200 | doi-access = free }} They are members of the rBAT family of mammalian proteins (TC #8.A.9).

Most S. cerevisiae amino acid permeases are members of the APC family. The majority of these permeases belong to the YAT sub-family (2.A.3.10) and they have a broad range of overlapping specificities. Two additional permeases belong to the LAT sub-family (2.A.3.8.4 and 2.A.3.8.16) and support methionine and cysteine intake. The final one identified is an ACT sub-family (2.A.3.4.3) member, a GABA permease, present in both cell and vacuolar membranes; all others are found only in the cell membrane.{{Cite journal |last1=Bianchi |first1=Frans |last2=van’t Klooster |first2=Joury S. |last3=Ruiz |first3=Stephanie J. |last4=Poolman |first4=Bert |date=2019-10-16 |title=Regulation of Amino Acid Transport in Saccharomyces cerevisiae |journal=Microbiology and Molecular Biology Reviews |volume=83 |issue=4 |pages=e00024–19 |doi=10.1128/MMBR.00024-19 |issn=1092-2172 |pmc=7405077 |pmid=31619504}}

Two APC family members, LAT1 and LAT2 (TC #2.A.3.8.7), transport a neurotoxicant, the methylmercury-L-cysteine complex, by molecular mimicry.{{cite journal | vauthors = Simmons-Willis TA, Koh AS, Clarkson TW, Ballatori N | title = Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2 | journal = The Biochemical Journal | volume = 367 | issue = Pt 1 | pages = 239–46 | date = October 2002 | pmid = 12117417 | pmc = 1222880 | doi = 10.1042/bj20020841 }}

Hip1 of S. cerevisiae (TC #2.A.3.1.5) has been implicated in heavy metal transport.

=Subfamilies=

Subfamilies of the APC family, and the proteins in these families, can be found in the Transporter Classification Database:

2.A.3.1: The Amino Acid Transporter (AAT) Family
2.A.3.2: The Basic Amino Acid/Polyamine Antiporter (APA) Family
2.A.3.3: The Cationic Amino Acid Transporter (CAT) Family
2.A.3.4: The Amino Acid/Choline Transporter (ACT) Family
2.A.3.5: The Ethanolamine Transporter (EAT) Family
2.A.3.6: The Archaeal/Bacterial Transporter (ABT) Family
2.A.3.7: The Glutamate:GABA Antiporter (GGA) Family
2.A.3.8: The L-type Amino Acid Transporter (LAT) Family (Many LAT family members function as heterooligomers with rBAT and/or 4F2hc (TC #8.A.9))
2.A.3.9: The Spore Germination Protein (SGP) Family
2.A.3.10: The Yeast Amino Acid Transporter (YAT) Family
2.A.3.11: The Aspartate/Glutamate Transporter (AGT) Family
2.A.3.12: The Polyamine:H+ Symporter (PHS) Family
2.A.3.13: The Amino Acid Efflux (AAE) Family
2.A.3.14: The Unknown APC-1 (U-APC1) Family
2.A.3.15: The Unknown APC-2 (U-APC2) Family

Structure and function

Based on 3-D structures of APC superfamily members, Rudnick (2011) has proposed the pathway for transport and suggested a "rocking bundle" mechanism.{{cite journal | vauthors = Forrest LR, Rudnick G | title = The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters | journal = Physiology | volume = 24 | issue = 6 | pages = 377–86 | date = December 2009 | pmid = 19996368 | pmc = 3012352 | doi = 10.1152/physiol.00030.2009 }}{{cite journal | vauthors = Rudnick G | title = Cytoplasmic permeation pathway of neurotransmitter transporters | journal = Biochemistry | volume = 50 | issue = 35 | pages = 7462–75 | date = September 2011 | pmid = 21774491 | pmc = 3164596 | doi = 10.1021/bi200926b }}