Significant findings about protein architecture may aid in drug design, generati

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Significant findings about protein architecture may aid in drug design,

generation of nanomaterials

http://www.eurekalert.org/pub_releases/2010-04/asfb-sfa040910.php

Researchers in Singapore are reporting this week that they have gleaned key

insights into the architecture of a protein that controls iron levels in almost

all organisms. Their study culminated in one of the first successful attempts to

take apart a complex biological nanostructure and isolate the rules that govern

its natural formation.

The Nanyang Technological University team's work on the protein ferritin, the

results of which appear in this week's issue of the Journal of Biological

Chemistry, is expected to have significant ramifications on the fields of drug

design and nanomaterials.

" Engineering the structure of a protein is one of the ultimate dreams of

structural biologists, " wrote one of the journal's peer reviewers, " and

approaching that dream is greatly enabled through studies aimed at finding out

what governs the nanoarchitecture of the protein. "

n P. Orner, the assistant professor who oversaw the team's work, described

the protein ferritin as a potential model for explaining complicated protein

structure in general.

Across the biological kingdoms, ferritin regulates the distribution of iron,

which is necessary for a number of cellular functions but also forms reactive

ions that can be lethal to cells. Shaped like a spherical nanocage, ferritin is

made up of 24 proteins, and it sequesters the reactive iron ions in its hollow

interior. In humans, ferritin prevents iron deficiency and overload.

" The rules that govern self-assembling nanosystems, like the ferritin model, are

poorly understood, " Orner explained. " We systematically analyzed the

interactions between the 24 ferritin units that make up the nanocage and

identified the hot spots that are crucial to the cage's formation. "

Their goal was to discover which amino acids are responsible for assembling the

cage, and they found that it is possible to both disassemble ferritin by

removing single side chains of amino acids and, surprisingly, to stabilize the

structure by removing other side chains.

Understanding the assembly of the nanocage could open the door to drug design

that will disrupt the structure and function of defective proteins that cause or

contribute to disease. It also may aid in the creation of biological

nanostructures in which scientists can grow special particles and materials with

a variety of properties and applications.

" Cell biology provides many structures that are on the nanoscale and have

amazing complexity and symmetry, " Orner said. " The problem is that many of these

structures are, like ferritin, self-assembled proteins, and, if we are going to

use them for nanomaterials applications, we need to understand the fundamentals

that make them form this way naturally. "

Orner and his team members are particularly interested in growing nanoparticles

of precise dimensions inside ferritin shells. Already, they have developed a new

method to grow gold nanoparticles in them.

" Slight deviations in size or shape can radically change nanoparticles'

properties, particularly in the case of metals and semiconductors, " Orner said.

" Our ferritin proteins are hollow, so, when we grow mineral or metal clusters

inside them, the growth stops when the nanoparticles reach the limits of the

protein shell. "

By studying the rules that control the folding and assembly of such a protein in

nature, Orner said, the investigators hope to be able to manipulate them one day

to create new proteins with novel sizes and shapes and, therefore, generate

nanoparticles of novel sizes and shapes inside them.

" Those nanoparticles could be used for in-vitro assays to do high-throughput

drug screening of some protein-protein interactions involved in virus infection

and cancer, for example, " he said.

Orner's team included doctoral students Yu Zhang and Rongli Fan, undergraduate

students Siti Raudah, Huihian Teo and Gwenda Teo, and scholar Xioming Sun. Their

research was funded by the Singapore Ministry of Education and Nanyang

Technological University.

Their resulting article has been named a " Paper of the Week " by the Journal of

Biological Chemistry, putting it in the top 1 percent of papers reviewed by the

editorial board in terms of significance and overall importance.