Proteins with Distinct Sites for Different Functions in the Same Domain

These are single domain or multidomain proteins (listed in Table 2.1) that use distinct spatial functional sites of a single domain for carrying out their primary and moonlighting function(s).

a-Enolase, Streptococcus pneumonia

a-Enolase (EC 4.2.1.11) from Streptococcus pneumoniae is a key glycolytic enzyme (Function 1) that is also expressed on the bacterial cell surface, where it binds to human plasminogen to facilitate the host invasion process during infection

Protein (organism)

Function 1

Function 2

Structure

Refs

Malate synthase (M. tuberculosis)

Malate synthase (EC 2.3.3.9)

Binds laminin

2GQ3

[39]

BirA (E. coli)

Biotin holoenzyme synthetase (EC 6.3.4.15)

Bio repressor

1BIB

[40]

MRDI (H. sapiens)

MTR-1-P isomerase (EC 5.3.1.23)

Mediator of cell invasion

4LDQ

[41]

Hexokinase 2 (S. cerevisiae)

Hexokinase 2 (EC 2.7.1.1)

Glucose sensor (interacts with transcriptional repressor Mig1)

1IG8

[42]

Neuropilin-I (H. sapiens)

Semaphorin binding

VEGF binding

2QQN

[43]

ATF2 (H. sapiens)

Transcription factor

DNA damage response

1T2K

[44]

Table 2.3 Proteins using the same residues for different functions.

Protein (organism)

Function 1

Function 2

Structure

Refs

GAPDH (E. coli)

GAPDH (EC 1.2.1.12)

NAD ribosylating activity

1DC5

[45]

Leukotriene A-4 hydrolase (H. sapiens)

Leukotriene A-4 hydrolase (EC 3.3.2.6)

Aminopeptidase (EC 3.4.11.24)

2R59

[46]

Hemagglutinin

(Paramyxovirus)

Hemagglutinin binding

Neuraminidase (EC 3.2.1.18)

1E8T

[47]

Table 2.4 Proteins using different residues in the same/overlapping site for different functions.

Protein (organism)

Function 1

Function 2

Structure

Refs

Phosphoglucose isomerase (0. cuniculus,

H. sapiens)

Phosphoglucose isomerase (EC 5.3.1.9)

Autocrine motility factor, neuroleukin, differentiation, and maturation mediator

  • 1DQR,
  • 1IAT

[48, 49]

Fructose-bisphosphate

aldolase

(P. falciparum)

Fructose-bisphosphate aldolase (EC 4.1.2.13)

Attaches actin to trap proteins

2PC4

[50]

Gpx4 (H. sapiens)

Phospholipid hydroperoxide glutathione peroxidase (EC 1.11.1.12)

Polymerized form has structural role in spermatozoa

2OBI

[51]

S1O ribosomal/ protein (E. coli)

Component of ribosomal 30S subunit

Part of transcription

antitermination

complex

1O9J

[52]

Lens crystallin/retinal DH (E. edwardii)

Lens crystallin

Retinal DH (EC 1.2.1.3)

1O9J

[53]

Table 2.5 Proteins using different folds for different functions.

Protein (organism)

Function 1

Function 2

Structure

Refs

RfaH (E. coli)

Lymphotactin (Ltn) (H. sapiens)

Transcription factor

Chemokine (activates XCR1)

Translational regulator

Binds cell-surface glycosaminoglycans

2OUG, 2LCL 2JP1

[54, 55] [56]

a-Enolase. (a) Single chain of Enolase showing the enzyme active site in blue and the plasminogen-binding site in red

Figure 2.3 a-Enolase. (a) Single chain of Enolase showing the enzyme active site in blue and the plasminogen-binding site in red. (b) Enolase monomer displayed as surface. Different domains are colored in gray and orange (PDB:1W6T). (See color plate section for the color representation of this figure.)

(Function 2) [31]. The protein is known to exist in an octameric state both in the cytoplasm and on the cell surface. Each monomer of a-enolase consists of a 2-layer ap sandwich domain and a TIM barrel domain (Fig. 2.3). The structurally conserved a-enolase active site is located in the TIM barrel which comprises the catalytic residues Glu164, Glu205, and Lys342 in S. pneumoniae, which are located in a pocket. Two plasminogen-binding sites have also been found in the TIM barrel domain at sites distinct from the active site that includes a nine- residue internal motif (248 FYDKERKYV256) and terminal lysine residues (433KK434). The former site has been shown to have a more important role in interacting with plasminogen than the latter. The last lysine residue is not included in the structure as it is disordered.

 
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