Phenylalanyl-tRNA synthetase

Figures & data

Table 1 Classification of aaRSs

Class	Subclass (subunit organization)	Enzymes	Signature motif	Catalytic domain architecture	Site of aminoacylaion
Class I	a (monomeric)	CysRS, lleRS, LeuRS, MetRS^a, and ValRS
	b (monomeric) c (homodimeric)	ArgRS, GlnRS, GluRS, and LysRS l^b TrpRS, and TyrRS	HIGH, and KMSKS	Rossmann fold	2’ OH
Class II	a (homodimeric)	GlyRS^c, HisRS, ProRS, SerRS, and ThrRS
	b (homodimeric)	AsnRS, AspRS, and LysRS II^b	Motif 1, motif 2, and motif 3	Antiparallel fold	3’ OH (except PheRS)
	c (tetrameric)	AlaRS (homotetramer)^d, GlyRS (heterotetramer)^c, PheRS (heterotetramer)^e, PylRS (homodimer), and SepRS (homotetramer)

Notes:

a MetRS also exists in homodimeric form under same subclass.

b LysRS is present in both the classes.

c GlyRS exists in two different forms in two subclasses.

d AlaRS also exists in monomeric form under same subclass.

e PheRS also exists in monomeric form under same subclass. Adapted from Klipcan L, Finarov I, Moor N, Safro MG. Structural aspects of phenylalanylation and quality control in three major forms of phenylalanyl-tRNA synthetase. J Amino Acids. 2010;2010:983503. Copyright © 2010 Liron Klipcan et al.⁷

Abbreviations: aaRSs, aminoacyl-tRNA synthetases; CysRS, cysteinyl-tRNA synthetase; IleRS, isoleucyl-tRNA synthetase; LeuRS, leucyl-tRNA synthetase; MetRS, methionyl-tRNA synthetase; ValRS, valyl-tRNA synthetase; ArgRS, arginyl-tRNA synthetase; GlnRS, glutaminyl-tRNA synthetase; GluRS, glutamyl-tRNA synthetase; LysRS, lysyl-tRNA synthetase; TrpRS, tryptophanyl-tRNA synthetase; TyrRS, tyrosyl-tRNA synthetase; GlyRS, glycyl-tRNA synthetase; HisRS, histidyl-tRNA synthetase; ProRS, prolyl-tRNA synthetase; SerRS, seryl-tRNA synthetase; ThrRS, threonyl-tRNA synthetase; AsnRS, asparginyl-tRNA synthetase; AspRS, aspartyl-tRNA synthetase; AlaRS, alanyl-tRNA synthetase; PheRS, phenylalanyl-tRNA synthetase; PylRS, pyrrolysyl-tRNA synthetase; SepRS, O-phosphoseryl-tRNA synthetase.

Figure 1 Schematic representation of localization and function of HctPheRS and HmtPheRS.

Abbreviations: FARS, HctPheRS encoding gene; FARS2, HmtPheRS encoding gene; HctPheRS, human cytosolic phenylalanyl-tRNA synthetase; HmtPheRS, human mitochondrial phenylalanyl-tRNA synthetase; Phe, phenylalanine; Tyr, tyrosine.

Table 2 Structural organisation of eubacterial PheRS

Subunit	Domain	Function
α	A0-A2	Catalytic site
β	B1	Helix-turn-helix (HTH) motif, interacts with DNA
β	B2	Secondary tRNA-binding site
β	B3-B4	Editing site
β	B5	Helix-turn-helix (HTH) motif, interacts with DNA
β	B6-B7	Involved in dimerization
^β	B8	Interacts with the anticodon of tRNA^Phe

Note: Data from Roy and Ibba.²⁵

Abbreviation: PheRS, phenylalalnyl-tRNA synthetase.

Table 3 Domain organisation divergence between the kingdoms

Kingdom	Subunit	Chain length	Sub-domain	References
Eubacteria	α	350 aa	A0-A2	23
	^β	785 aa	B1–B8
Archaea	α	501 aa	A1–A2	28
	^β	574 aa	B1, B3-B7
Eukarya	α	508 aa	A1-A2	26
(cytosolic)	^β	589 aa	B1, B3-B7

Figure 2 Crystal structures of HctPheRS and ttPheRS.

Notes: (A) Adapted from Structure; 18(3); Finarov I, Moor N, Kessler N, Klipcan L, Safro MG; Structure of human cytosolic phenylalanyl-tRNA synthetase: evidence for kingdom-specific design of the active sites and tRNA binding patterns; 343–353; Copyright © 2010; with permission from Elsevier.²⁷ Crystal structure of HctPheRS (PDB ID: 3L4G). Domain architecture of the two αβ heterodimers are shown with one heterodimer lacking the N-terminal domain of the α subunit. α subunit: N-terminal domain containing DBD-1, DBD-2, and DBD-3 colored green, the linker region colored yellow, catalytic domains A1 and A2 colored red and blue, respectively. β subunit: B1, B3, B4 domains colored grey, B5 domain colored brown, B6 domain colored purple, and the B7 domain colored cyan. (B) Adapted from Moor N, Kotik-Kogan O, Tworowski D, Sukhanova M, Safro M. The crystal structure of the ternary complex of phenylalanyl-tRNA synthetase with tRNAPhe and a phenylalanyl-adenylate analogue reveals a conformational switch of the CCA end. Biochemistry. 2006; 45(35):10572–10583.³³ Crystal structure of ttPheRS complexed with tRNA^Phe and PheOH-AMP (PDB ID: 2iy5). Domain architecture of one αβ heterodimer is shown with N-terminal coiled coil of α subunit colored green, catalytic domains A1 and A2 colored red and blue, respectively, β subunit domain B1 colored grey, B2 domain colored pink, B3 domain colored orange, B4 domain colored olive green, B5 domain colored brown, B6 domain colored purple, B7 domain colored cyan, and B8 domain colored yellow.
Abbreviations: DBD, DNA binding domain; HctPheRS, human cytosolic phenylalanyl-tRNA synthetase; ttPheRS, Thermus thermophiles phenylalanyl-tRNA synthetase; PDB, Protein Data Bank; PheOH-AMP, phenylalaninyl-adenylate.

Figure 3 Crystal structures of HmtPheRS.

Notes: (A) Adapted from Structure; 16(7); Klipcan L, Levin I, Kessler N, Moor N, Finarov I, Safro M; The tRNA-induced conformational activation of human mitochondrial phenylalanyl-tRNA synthetase; 1095–1104; Copyright © 2008; with permission from Elsevier.⁴⁷ Crystal structure of HmtPheRS (PDB ID: 3CMQ).⁴⁷ (B) Adapted from J Mol Biol; 415(3); Klipcan L, Moor N, Finarov I, Kessler N, Sukhanova M, Safro MG; Crystal structure of human mitochondrial PheRS complexed with tRNA(Phe) in the active “open” state; 527–537; Copyright © 2012; with permission from Elsevier.⁴⁸ Crystal structure of HmtPheRS complexed with tRNA^Phe (PDB ID: 3TUP).⁴⁸ Domain architecture of HmtPheRS with the N-terminal domain colored green, the catalytic domain colored red, the linker region colored purple, and the anticodon binding domain colored yellow.
Abbreviation: HmtPheRS, human mitochondrial phenylalanyl-tRNA synthetase.

Table 4 Disease-related mutations of HmtPheRS

Mutation	Exon	Amino acid change	Domain	Disease	Ethnicity	Amino acid conservation	References
c.431A>G	3	Y144C	CD	Developmental delay, myoclonus seizures	Saudi Arabian	Conserved	122,123
c.986T>C	5	1329T	CD	Alpers encephalopathy	Finnish	Conserved	122
c.1172A>T	6	D391v	ABD	Alpers encephalopathy	Finnish	Conserved	122
c.973G>T	5	D325Y	CD	Infantile-onset epilepsy	British	Conserved	124
c.1255C>T	7	R419C	ABD	Global developmental delay, dysarthria and tremor	Mixed European	Not conserved	125

Abbreviations: ABD, anticodon binding domain; CD, catalytic domain; HmtPheRS, human mitochondrial phenylalanyl-tRNA synthetase.

Figure 4 Sites of genetic mutations in HmtPheRS.

Abbreviations: HmtPheRS, human mitochondrial phenylalanyl-tRNA synthetase; MTS, mitochondrial targeting sequence.

Table 5 Antisynthetase antibodies

aaRS (antigen)	Class	Autoantibody	References
Phenylalanyl-tRNA synthetase	II	Zo	127
Histidyl-tRNA synthetase	II	Jo-1	128
Threonyl-tRNA synthetase	II	PL-7	129
Alanyl-tRNA synthetase	II	PL-12	130
Isoleucyl-tRNA synthetase	I	OJ	131
Glycyl-tRNA synthetase	II	EJ	131
Asparaginyl-tRNA synthetase	II	KS	132
Tyrosyl-tRNA synthetase	I	Ha	133

Finarov I, Moor N, Kessler N, Klipcan L, Safro MG. Structure of human cytosolic phenylalanyl-tRNA synthetase: evidence for kingdom-specific design of the active sites and tRNA binding patterns. Structure. 2010;18(3):343–353.

 Web of Science ®Google Scholar

Moor N, Kotik-Kogan O, Tworowski D, Sukhanova M, Safro M. The crystal structure of the ternary complex of phenylalanyl-tRNA synthetase with tRNAPhe and a phenylalanyl-adenylate analogue reveals a conformational switch of the CCA end. Biochemistry. 2006;45(35):10572–10583.

 Google Scholar

Klipcan L, Levin I, Kessler N, Moor N, Finarov I, Safro M. The tRNA-induced conformational activation of human mitochondrial phenylalanyl-tRNA synthetase. Structure. 2008;16(7):1095–1104.

 Web of Science ®Google Scholar

Klipcan L, Moor N, Finarov I, Kessler N, Sukhanova M, Safro MG. Crystal structure of human mitochondrial PheRS complexed with tRNA(Phe) in the active “open” state. J Mol Biol. 2012;415(3):527–537.

 Web of Science ®Google Scholar