Unraveling the components of protein translocation pathway in human malaria parasite Plasmodium falciparum

doi:10.1016/j.abb.2007.08.031

Archives of Biochemistry and Biophysics

Volume 467, Issue 2, 15 November 2007, Pages 249-260

https://doi.org/10.1016/j.abb.2007.08.031 Get rights and content

Abstract

The targeting and translocation of proteins is an essentially required and conserved process in all the living organisms. This complex process involves multiple steps and requires a variety of factors before the protein reaches its final destination. The major components of translocation machinery are signal recognition particle (SRP) and secretory (Sec) complex. These are composed of highly conserved components. SRP contains SRP RNA and other polypeptides such as SRP9, SRP14, SRP19 and SRP54. Sec complex is composed of Sec61αβγ, Sec62 and Sec63. In this review using bioinformatics approach we have shown that the P. falciparum genome contains the homologues for all of these and other factors such as SRP receptor, and TRAM (translocation associated membrane protein), which are required for post- and co-translational protein translocation. We have also shown the various steps of translocation in a hypothetical model.

Section snippets

Components of protein targeting in P. falciparum

The eukaryotic SRP is composed of a ∼300 nucleotide 7S RNA and the following SRP proteins with masses of 9, 14, 19, 54, 68 and 72 kDa. These proteins are bound and organized in two domains of SRP RNA, the S-domain and the Alu-domain [12], [13]. Studies in mammalian and yeast cells have shown that SRP assembles via ‘SRP-54-late’ pathway in which all the components of SRP except SRP54 are imported into the nucleolus where they bind the SRP RNA [14], [15], [16], [17], [18]. This incompletely

SRP RNA

The SRP RNA of P. falciparum is about 300 nucleotides in length and has been described in detail previously [21], [22]. Generally the SRP RNA contains the well-characterized Alu (small) and S (large) domains and the helix 2–8 and helix 12 but in P. falciparum, helix 3 is extended and is composed of several base pairs [22]. In Saccharomyces cerevisiae SRP RNA it has been reported that additional insertions in the Alu domain are present [23]. The Alu domain of P. falciparum SRP RNA is different

SRP9 and SRP14

These are small proteins bound to the Alu domain and the 5′ and 3′ extremities of the SRP RNA. The SRP9 and SRP14 proteins form a heterodimer, which is involved in the SRP-mediated translation arrest or retardation. The two proteins possess only limited sequence homology but it has been shown in Mus musculus that SRP9 and SRP14 are structurally homologous [25]. The two proteins contribute to the formation of physiological dimer [13]. It has been shown in yeast that SRP14 is directly involved in

SRP19 and SRP54

SRP54 is an important component and is the only protein subunit, which is conserved in all SRPs and co-ordinates the interaction between the SRP receptor, the ribosome and the translocon [1], [5]. The fact that all the SRPs contain an SRP54 homologue reflects the indispensable function of this protein. Studies have shown that SRP19 induces a structural change in the S-domain of SRP RNA and facilitates its binding to SRP54 [1]. The mammalian SRP19 in its unbound state is unstructured and

SRP receptor

It is well established now that the co-translational protein targeting depends mainly on the coordinated action of the two components, which are SRP54 and SRPRα and this interaction of SRP54 and SRPR regulates the protein targeting process and ensures the directionality. SRPRα is a GTPase and is closely related in structure, sequence and function to the GTPase domain of SRP54 but the sequence of SRPRβ is not closely related to SRP54. SRPRα associates with the β subunit of SRPR (SRPRβ), which is

TRAM (Translocation associated membrane protein)

TRAM has been identified as an essential component, which is required for properly assembling a translocationally paused nascent polypeptide chain and it is responsible for efficient translocation of various secretory proteins [37]. It has been demonstrated that TRAM serves to limit the cytosolic exposure of paused secretory proteins to specified domains, preventing other regions of the nascent chain from being inappropriately revealed to the cytoplasm therefore TRAM regulates which domains of

Sec complex

The passage of the nascent chain through the ER membrane is mediated by highly conserved protein conducting channel (PCC). It has been suggested that SRPR catalyses the transfer of the ribosome/nascent polypeptide complex from SRP to the Sec61 complex translocon. This results in the release of the translation arrest and subsequently the chain elongation drives the growing polypeptide by way of the pore into the ER. The core of sec complex of PCC is composed of heteromeric protein complex Sec61α

Conclusions and future prospects

The importance of components of this machinery has been documented in a recent study in humans, where it has been reported that mutations in the components of transport machinery cause various human diseases, which further suggests that this is an important and vital pathway [43]. Using bioinformatics approach we have shown that the components of protein translocation machinery are present and well-conserved in P. falciparum. Since the parasite targets the proteins to various compartments

Acknowledgments

The author is grateful to Yash Gupta and Arun Pradhan for their help in preparation of figures. The work in RTs laboratory is supported by Department of Biotechnology grant. Infrastructural support from the Department of Biotechnology, Government of India is gratefully acknowledged.

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MinireviewUnraveling the components of protein translocation pathway in human malaria parasite Plasmodium falciparum

Abstract

Section snippets

Components of protein targeting in P. falciparum

SRP RNA

SRP9 and SRP14

SRP19 and SRP54

SRP receptor

TRAM (Translocation associated membrane protein)

Sec complex

Conclusions and future prospects

Acknowledgments

Arch. Biochem. Biophys.

Trends Parasitol.

Biochem. Biophys. Res. Commun.

Curr. Biol.

Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

Trends Mol. Med.

Annu. Rev. Biochem.

EMBO J.

J. Cell Biol.

Mol. Memb. Biol.

Biochem. Cell Biol.

Bull. World Health Organ.

Am. J. Trop. Med. Hyg.

PLoS Biol.

Minireview
Unraveling the components of protein translocation pathway in human malaria parasite Plasmodium falciparum